Aminiothiazoles and their uses

ABSTRACT

The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of diseases particularly bacterial infections.

BACKGROUND

Since the discovery of penicillin, pharmaceutical companies haveproduced a number of antibacterial agents to combat a wide variety ofbacterial infections. In the past several years, there has been rapidemergence of bacterial resistance to several of these antibiotics. Themultidrug resistance among these bacterial pathogens may also be due tomutation leading to more virulent clinical isolation. Perhaps the mostdisturbing occurrence has been the acquisition of resistance tovancomycin, an antibiotic generally regarded as the agent of last resortfor serious Gram-positive infections.

This is true especially of some Gram-positive pathogen groups, such asstaphylococci, pneumococci and enterococci (S. Ewig et al.;Antibiotika-Resistenz bei Erregern ambulant erworbenerAtemwegsinfektionen (Antibiotic resistance in pathogens ofoutpatient-acquired respiratory tract infections); Chemother. J. 2002,11, 12-26; F. Tenover; Development and spread of bacterial resistance toantimicrobial agents: an overview; Clin. Infect. Dis. 2001 Sep. 15, 33Suppl. 3, 108-115) as well as Staphylococcus, Streptococcus,Mycobacterium, Enterococcus, Corynebacterium, Borrelia, Bacillus,Chlamydia, Mycoplasma, and the like.

A problem of equally large dimension is the increasing incidence of themore virulent, methicillin-resistant Staphylococcus aureas (MRSA) amongclinical isolates found worldwide. As with vancomycin resistantorganisms, many MRSA strains are resistant to most of the knownantibiotics, but MRSA strains have remained sensitive to vancomycin.However, in view of the increasing reports of vancomycin resistantclinical isolates and growing problem of bacterial resistance, there isan urgent need for new molecular entities effective against the emergingand currently problematic Gram-positive organisms.

This growing multidrug resistance has recently rekindled interest in thesearch for new structural classes of antibiotics that inhibit or killthese bacteria.

SUMMARY OF THE INVENTION

There remains a need for new treatments and therapies for bacterialinfections. There is also a need for compounds useful in the treatmentor prevention or amelioration of one or more symptoms of bacterialinfections. Furthermore, there is a need for methods for modulating theactivity of the elongation factor EF-Tu, using the compounds providedherein.

In one aspect, the invention provides a compound of formula I:

In another aspect, the invention provides a method of treating abacterial infection wherein the treatment includes administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of formula I, II, III, IV, V, or VI, such that the bacterialinfection is treated.

In another aspect, the invention provides a method of treating an EF-Tuassociated-state wherein the treatment includes administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of formula I, II, III, IV, V, or VI, such that the EF-Tuassociated state is treated.

In still another aspect, the invention provides a method of treating,inhibiting or preventing the activity of EF-Tu in a subject in needthereof, which includes administering to the subject a pharmaceuticallyacceptable amount of a compound of formula I, II, III, IV, V, or VI. Inone embodiment, a bacterial infection is treated in a subject in needthereof.

In another aspect, the invention provides a method of treating,inhibiting or preventing the activity of bacteria in a subject in needthereof, which includes administering to the subject a pharmaceuticallyacceptable amount of a compound of formula I, II, III, IV, V, or VI,wherein the compound interacts with any target in the life cycle of thebacteria. In one embodiment, the target is EF-Tu.

In another aspect, the invention provides a method of treating abacterial infection in a subject, wherein the treatment includesadministering to a subject in need thereof a pharmaceutically acceptableamount of a compound of the formula I, II, III, IV, V, or VI, and apharmaceutically acceptable carrier, such that the bacterial infectionis treated.

In still another aspect, the invention provides a method of treating abacterial infection wherein the treatment includes administering to asubject in need thereof a pharmaceutically effective amount of acompound of the formula I, II, III, IV, V, or VI, in combination with apharmaceutically effective amount of an additional therapeutic agent,such that the bacterial infection is treated. In one embodiment, thecompound of the formula I, II, III, IV, V, or VI and the otherpharmaceutical agent are administered as part of the same pharmaceuticalcomposition. In another embodiment, the compound of the formula I, II,III, IV, V, or VI and the other therapeutic agent are administered asseparate pharmaceutical compositions, and the compound is administeredprior to, at the same time as, or following administration of the otheragent.

In another aspect, the invention provides a packaged bacterial infectiontreatment, comprised of formula I, II, III, IV, V, or VI, packaged withinstructions for using an effective amount of the compound to treat abacterial infection.

In another aspect, the invention provides a method of treating acne insubject in need thereof, wherein the treatment includes administering tothe subject a pharmaceutically acceptable amount of a compound offormula I, II, III, IV, V, or VI.

In yet another aspect, the invention provides a pharmaceuticalcomposition which includes a compound of formula I, II, III, IV, V, orVI, and at least one pharmaceutically acceptable carrier or diluent.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds, e.g., thiopeptide compounds,and intermediates thereto, as well as pharmaceutical compositionscontaining the compounds for use in treatment of bacterial infection.This invention is also directed to the compounds of the invention orcompositions thereof as modulators of the elongation factor EF-Tu. Thecompounds are particularly useful in interfering with the life cycle ofbacteria and in treating or preventing a bacterial infection orphysiological conditions associated therewith. The present invention isalso directed to methods of combination therapy for inhibiting EF-Tuactivity in cells, or for treating or preventing a bacterial infectionin patients using the compounds of the invention or pharmaceuticalcompositions, or kits thereof.

In one aspect, the invention provides compounds of the formula I:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof;

wherein

R¹ is —Z—CO₂H and -A-Z—CO₂H;

R^(1a) is hydrogen, —Z—CO₂H, and -A-Z—CO₂H, wherein if R^(1a) ishydrogen, then the Z residue of R¹ is substituted by at least two CO₂Hgroups; or

R¹ and R^(1a), taken in combination, form a saturated, partiallyunsaturated or aromatic heterocycle having 4 to 7 ring atoms and having0-3 additional ring heteroatoms selected from N, O and S, wherein theheterocycle is substituted by at least two residues independentlyselected from CO₂H, —Z—CO₂H, and -A-Z—CO₂H;

A is independently selected at each occurrence from the group consistingof a —C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—, —C(H)═N—,—S(O)₂N(R^(8a))—, and —S(O)N(R^(8a))—;

Z is C₁-C₁₀alkylene, C₃-C₈cycloalkylene, C₃-C₈heterocycloalkylene,phenylene, or 5-6 membered heteroarylene, each of which is optionallysubstituted with one or more groups independently selected fromC₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, amino, mono- and di-C₁-C₆alkylamino,C(O)0H, or halogen;

R^(2a) is selected from the group consisting of H, substituted orunsubstituted alkyl, OH, OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ andN(R^(8a))₂;

R^(2b) is selected from the group consisting of absent, H and alkyl, orR^(2a) and R^(2b) may together form ═O or ═NH;

R³ an R¹² are each, independently, selected from the group consisting ofH, halogen, OR^(4b), -A-J, and N(R^(8a))₂;

R^(4a) is selected from the group consisting of H, and alkyl;

R^(4b) is selected from the group consisting of alkyl and—(CH₂—CH₂—O—)_(n)—R⁹, wherein n is an integer of 1-500, 1,000, 2,000,3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000or is a mean of a plurality of integers having a value of 1-500, 1,000,2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or60,000;

R⁵ is selected from the group consisting of H, alkyl, and R^(4b);

J is selected from the group consisting of H, F, O-alkyl, N(R^(8a))₂,N⁺(R^(8a))₃, N(R^(8a))C(O)alkyl, CO₂H, C(═O)N(R^(8a))₂, CO₂-alkyl,P(O)(OH)₂, P(O)(O-alkyl)₂, and a substituted nitrogen-containingheterocycle;

R^(8a) is absent, or selected from the group consisting of H, -(alkyl)-,-(cycloalkyl)-, C(alkyl)-2-J, —R^(4b), wherein R^(8a) can also cyclizewith the atom to which R^(8a) is bonded to form a 3, 4, 5, 6 or7-membered ring that is aromatic or non-aromatic and may contain one ormore heteroatoms, wherein the ring may be further substituted one ormore times with substitutents that are the same or different; and

R⁹ is selected from the group consisting of H, alkyl and CH₂CO₂H.

Certain compounds of formula I provided herein include compounds offormula II and formula III:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof.

Certain compounds of formula III include those compounds represented byformula IV:

Certain compounds of formula I include those compounds represented byformula V:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof, wherein

D represents a five or six membered heterocyclic ring which is saturatedor aromatic, which ring comprises 0-2 additional ring heteroatomsselected from N, O or S.

Certain compounds of formula IV include those compounds represented byformula V-a:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof, wherein

D represents a five or six membered heterocyclic ring which is saturatedor aromatic, which ring comprises 0-2 additional ring heteroatomsselected from N, O or S.

Certain preferred compounds of Formula I, III, or V include thosecompounds in which R^(2b), R^(4b) and R⁵ are H, and R^(4a) is CH₃. Otherpreferred compounds of Formula I include those compounds in whichR^(2b), R^(4b) and R⁵ are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃.

Certain compounds of formula V include those compounds represented byformula VI:

Certain compounds of formula I include those compounds represented byformula VI-a:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof, wherein

D represents a five or six membered heterocyclic ring which is saturatedor aromatic, which ring comprises 0-2 additional ring heteroatomsselected from N, O or S.

Certain preferred compounds of Formula III, IV, V, V-a, VI, VI-a includethose compounds in which

A is selected from the group consisting of —C(O)O—, C(O)—NH—, —C(O)—,—S(O)₂—, and —S(O)₂NH—; and

Z is independently selected at each occurrence from the group consistingof C₁-C₁₀alkylene,

Still other compounds of formula I provided herein include thosecompounds in which R^(2a) is OH or OAC.

Yet other compounds of formula I provided herein include those compoundsin which the core pyridine functionality is of the following N-oxideformula:

In yet another aspect, the invention provides compounds of the formulaVII:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof;

wherein

R¹ is —Z—CO₂H and -A-Z—CO₂H;

R^(1a) is hydrogen, —Z—CO₂H, and -A-Z—CO₂H, wherein if R^(1a) ishydrogen, then the Z residue of R¹ is substituted by at least two CO₂Hgroups; or

R¹ and R^(1a), taken in combination, form a saturated, partiallyunsaturated or aromatic heterocycle having 4 to 7 ring atoms and having0-3 additional ring heteroatoms selected from N, O and S, wherein theheterocycle is substituted by at least two residues independentlyselected from CO₂H, —Z—CO₂H, and -A-Z—CO₂H;

A is indepenendently selected at each occurrence from the groupconsisting of a —C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—,—C(H)═N—, —S(O)₂N(R^(8a))—, and —S(O)N(R^(8a))—;

Z is C₁-C₁₀alkylene, C₃-C₈cycloalkylene, C₃-C₈heterocycloalkylene,phenylene, or 5-6 membered heteroarylene, each of which is optionallysubstituted with one or more groups independently selected fromC₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, amino, mono- and di-C₁-C₆alkylamino,C(O)OH, or halogen;

R² is hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₀₋₆alkyl,C₃₋₇cycloalkylC₀₋₄alkyl, arylC₀₋₄alkyl, or a residue of the formula:

R^(2a) is selected from the group consisting of H, substituted orunsubstituted alkyl, OH, OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ andN(R^(8a))₂;

R^(2b) is selected from the group consisting of absent, H and alkyl, orR^(2a) and R^(2b) may together form ═O or ═NH;

R³ an R¹² are each, independently, selected from the group consisting ofH, halogen, OR^(4b), -A-J, and N(R^(8a))₂;

R^(4a) is selected from the group consisting of H, and alkyl;

R^(4b) is selected from the group consisting of alkyl and—(CH₂—CH₂-O—)_(n)—R⁹, wherein n is an integer of 1-500, 1,000, 2,000,3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000or is a mean of a plurality of integers having a value of 1-500, 1,000,2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or60,000;

R⁵ is selected from the group consisting of H, alkyl, and R^(4b);

J is selected from the group consisting of H, F, O-alkyl, N(R^(8a))₂,N⁺(R^(8a))₃, N(R^(8a))C(O)alkyl, CO₂H, C(═O)N(R^(8a))₂, CO₂-alkyl,P(O)(OH)₂, P(O)(O-alkyl)₂, and a substituted nitrogen-containingheterocycle;

R^(8a) is absent, or selected from the group consisting of H, -(alkyl)-,-(cycloalkyl)-, C(alkyl)-2-J, —R^(4b), wherein R^(8a) can also cyclizewith the atom to which R^(8a) is bonded to form a 3, 4, 5, 6 or7-membered ring that is aromatic or non-aromatic and may contain one ormore heteroatoms, wherein the ring may be further substituted one ormore times with substitutents that are the same or different; and

R⁹ is selected from the group consisting of H, alkyl and CH₂CO₂H.

Preferred embodiments of the compounds of the invention (includingpharmaceutically acceptable salts thereof, as well as enantiomers,stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof)are shown below in Table A and Table B, and are also considered to be“compounds of the invention.”

TABLE A  1.

 2.

 3.

 4.

 5.

 6.

 7.

 8.

 9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

TABLE B

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

In certain embodiments, the compound of the present invention is furthercharacterized as a modulator of EF-Tu, including a prokaryotic EF-Tu,and especially including a bacterial EF-Tu. In a preferred embodiment,the compound of the invention is an EF-Tu inhibitor.

As used herein, the term “bacterial infection(s)” includes, but is notlimited to, bacterial infections that occur in mammals, fish and birdsas well as disorders related to bacterial infections that may be treatedor prevented by administering antibiotics such as the compounds of thepresent invention. In addition to treating infections caused bymulti-drug resistant strains of Staphyloccocus aureus, Streptococcuspneumoniae, Mycobacterium tuberculosis and Enterococci, the compounds ofthe present invention are useful in treating infections caused by otherbacteria including, but not limited to, Clostridium difficile,Propionibacterium acnes, Bacteroides fagiles, Neisseria gonorrhoeae,Branhamella catarrhalis, Haemophilus influenzae, E. coli, Pseudomonasaeruginosa, Proteus vulgaris, Klebsiella pneumonia, and Chlamydiatrachomatis.

Such bacterial infections and disorders related to such infectionsinclude, but are not limited to, the following: acne, rosacea, skininfection, pneumonia, otitis media, sinusitus, bronchitis, tonsillitis,and mastoiditis related to infection by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus,Peptostreptococcus spp. or Pseudomonas spp.; pharynigitis, rheumaticfever, and glomerulonephritis related to infection by Streptococcuspyogenes, Groups C and G streptococci, Clostridium diptheriae, orActinobacillus haemolyticum; respiratory tract infections related toinfection by Mycoplasma pneumoniae, Legionella pneumophila,Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydiapneumoniae; uncomplicated skin and soft tissue infections, abscesses andosteomyelitis, and puerperal fever related to infection byStaphylococcus aureus, coagulase-positive staphylococci (i.e., S.epidermidis, S. hemolyticus, etc.), S. pyogenes, S. agalactiae,Streptococcal groups C-F (minute-colony streptococci), viridansstreptococci, Corynebacterium spp., Clostridium spp., or Bartonellahenselae; uncomplicated acute urinary tract infections related toinfection by S. saprophyticus or Enterococcus spp.; urethritis andcervicitis; sexually transmitted diseases related to infection byChlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum,Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseases relatedto infection by S. aureus (food poisoning and Toxic shock syndrome), orGroups A, S, and C streptococci; ulcers related to infection byHelicobacter pylori; systemic febrile syndromes related to infection byBorrelia recurrentis; Lyme disease related to infection by Borreliaburgdorferi; conjunctivitis, keratitis, and dacrocystitis related toinfection by C. trachomatis, N. gonorrhoeae, S. aureus, S. pneumoniae,S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacteriumavium complex (MAC) disease related to infection by Mycobacterium avium,or Mycobacterium intracellulare; gastroenteritis related to infection byCampylobacter jejuni; intestinal protozoa related to infection byCryptosporidium spp., odontogenic infection related to infection byviridans streptococci; persistent cough related to infection byBordetella pertussis; gas gangrene related to infection by Clostridiumperfringens or Bacteroides spp.; Skin infection by S. aureus,Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Further bacterial infections and disorders related to such infectionsthat may be treated or prevented in animals include, but are not limitedto, the following: bovine respiratory disease related to infection by P.haemolytica., P. multocida, Mycoplasma bovis, or Bordetella spp.; cowenteric disease related to infection by E. coli or protozoa (i.e.,coccidia, cryptosporidia, etc.), dairy cow mastitis related to infectionby S. aureus, S. uberis, S. agalactiae, S. dysgalactiae, Klebsiellaspp., Corynebacterium, or Enterococcus spp.; swine respiratory diseaserelated to infection by A. pleuropneumoniae., P. multocida, orMycoplasma spp.; swine enteric disease related to infection by E. coli,Lawsonia intracellularis, Salmonella spp., or Serpulina hyodyisinteriae;cow footrot related to infection by Fusobacterium spp.; cow metritisrelated to infection by E. coli; cow hairy warts related to infection byFusobacterium necrophorum or Bacteroides nodosus; cow pink-eye relatedto infection by Moraxella bovis, cow premature abortion related toinfection by protozoa (i.e., neosporium); urinary tract infection indogs and cats related to infection by E. coli; skin and soft tissueinfections in dogs and cats related to infection by S. epidermidis, S.intermedius, coagulase neg. Staphylococcus or P. multocida; dental ormouth infections in dogs and goats related to infection by Alcaligenesspp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacteriumspp., Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., Trichomonas spp. or Prevotella spp. Other bacterialinfections and disorders related to such infections that may be treatedor prevented in accord with the method of the present invention arereferred to in J. P. Sanford at al., “The Sanford Guide To AntimicrobialTherapy,” 26th Edition, (Antimicrobial Therapy, Inc., 1996).

Further bacterial infections and disorders related to such infectionsthat may be treated or prevented in animals include, but are not limitedto, central nervous system infections, external ear infections,infections of the middle ear, such as acute otitis media, infections ofthe cranial sinuses, eye infections, infections of the oral cavity, suchas infections of the teeth, gums and mucosa, upper respiratory tractinfections, lower respiratory tract infections, genitourinaryinfections, gastrointestinal infections, gynecological infections,septicemia, bone and joint infections, skin and skin structureinfections, bacterial endocarditis, burns, antibacterial prophylaxis ofsurgery, antibacterial prophylaxis in immunosuppressed patients, such aspatients receiving cancer chemotherapy, or organ transplant patients andchronic diseases caused by infectious organisms, e.g., arteriosclerosis.

Bacterial protein synthesis requires EF-Tu chaperone proteins. EF-Tu isone of the most abundant proteins in bacteria, as well as one of themost highly conserved, and in a number of species the gene is duplicatedwith identical function. When bound to GTP, EF-Tu can form a complexwith most aminoacylated tRNAs, loading the tRNA onto the ribosome. Inone embodiment, the bacterial infection is associated with the activityof EF-Tu. Without being bound by theory, it is believed that thedisruption of EF-Tu protein activity by the compounds of the inventionwill interfere with protein synthesis and thus bacterial function and/orproliferation. Because EF-Tu is highly conserved across Gram-positiveand Gram-negative bacteria, the compounds of the present invention areuseful for treating infections of both classes of bacteria.

As used herein, the term “EF-Tu-associated state” or “EF-Tu-associateddisorder” include disorders and states (e.g., a disease state) that areassociated with the activity of EF-Tu. A non-limiting example of anEF-Tu associated disorder is a bacterial infection in a subject.

The present invention includes treatment of bacterial infections, aswell as EF-Tu-associated disorders, as described above, but theinvention is not intended to be limited to the manner by which thecompound performs its intended function of treatment of a disease. Thepresent invention includes treatment of diseases described herein in anymanner that allows treatment to occur, e.g., bacterial infection.

In certain embodiments, the invention provides a pharmaceuticalcomposition of any of the compounds of the present invention. In arelated embodiment, the invention provides a pharmaceutical compositionof any of the compounds of the present invention and a pharmaceuticallyacceptable carrier or excipient of any of these compounds. In certainembodiments, the invention includes the compounds as novel chemicalentities.

In one embodiment, the invention includes a packaged bacterial infectiontreatment. The packaged treatment includes a compound of the inventionpackaged with instructions for using an effective amount of the compoundof the invention for an intended use.

The compounds of the present invention are suitable as active agents inpharmaceutical compositions that are efficacious particularly fortreating bacterial infections. The pharmaceutical composition in variousembodiments has a pharmaceutically effective amount of the presentactive agent along with other pharmaceutically acceptable excipients,carriers, fillers, diluents and the like. The phrase, “pharmaceuticallyeffective amount” as used herein indicates an amount necessary toadminister to a host, or to a cell, issue, or organ of a host, toachieve a therapeutic result, especially an anti-bacterial infectioneffect, e.g., inhibition of proliferation of a bacterium, or of anyother bacterial infection.

In other embodiments, the present invention provides a method forinhibiting the activity of an EF-Tu protein. The method includescontacting a cell with any of the compounds of the present invention. Ina related embodiment, the method further provides that the compound ispresent in an amount effective to selectively inhibit the activity of anEF-Tu protein.

In other embodiments, the present invention provides a use of any of thecompounds of the invention for manufacture of a medicament to treat abacterial infection in a subject.

In other embodiments, the invention provides a method of manufacture ofa medicament, including formulating any of the compounds of the presentinvention for treatment of a subject.

DEFINITIONS

The term “treat,” “treated,” “treating” or “treatment” includes thediminishment or alleviation of at least one symptom associated or causedby the state, disorder or disease being treated. In certain embodiments,the treatment comprises the induction of a bacterial infection, followedby the activation of the compound of the invention, which would in turndiminish or alleviate at least one symptom associated or caused by thebacterial infection being treated. For example, treatment can bediminishment of one or several symptoms of a disorder or completeeradication of a disorder.

The term “subject” is intended to include organisms, e.g., prokaryotesand eukaryotes, which are capable of suffering from or afflicted with abacterial infection. Examples of subjects include mammals, e.g., humans,dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, andtransgenic non-human animals. In certain embodiments, the subject is ahuman, e.g., a human suffering from, at risk of suffering from, orpotentially capable of suffering from a bacterial infection, and fordiseases or conditions described herein. In another embodiment, thesubject is a cell.

The language “EF-Tu-modulating compound,” “modulator of EF-Tu” or “EF-Tuinhibitor” refers to compounds that modulate, e.g., inhibit, orotherwise alter, the activity of EF-Tu. Examples of EF-Tu-modulatingcompounds include compounds of formula I, II, III, IV and V, as well asTable A and Table B (including pharmaceutically acceptable saltsthereof, as well as enantiomers, stereoisomers, rotamers, tautomers,diastereomers, atropisomers or racemates thereof).

Additionally, a method of the invention includes administering to asubject an effective amount of an EF-Tu-modulating compound of theinvention, e.g., EF-Tu-modulating compounds of Formula I, II, III, IVand V, as well as Table A and Table B (including pharmaceuticallyacceptable salts thereof, as well as enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof).

The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.The term “alkyl” also includes alkenyl groups and alkynyl groups.Furthermore, the expression “C_(x)-C_(y)-alkyl”, wherein x is 1-5 and yis 2-10 indicates a particular alkyl group (straight- or branched-chain)of a particular range of carbons. For example, the expressionC₁-C₄-alkyl includes, but is not limited to, methyl, ethyl, propyl,butyl, isopropyl, tert-butyl, isobutyl and sec-butyl. Moreover, the termC₃₋₆-cycloalkyl includes, but is not limited to, cyclopropyl,cyclopentyl, and cyclohexyl. As discussed below, these alkyl groups, aswell as cycloalkyl groups, may be further substituted. “C₀-C_(n)alkyl”refers to a single covalent bond (C₀) or an alkyl group having from 1 ton carbon atoms; for example “C₀-C₄alkyl” refers to a single covalentbond or a C₁-C₄alkyl group; “C₀-C₈alkyl” refers to a single covalentbond or a C₁-C₈alkyl group. In some instances, a substituent of an alkylgroup is specifically indicated. For example, “C₁-C₄hydroxyalkyl” refersto a C₁-C₄alkyl group that has at least one hydroxy substituent.

“Alkylene” refers to a divalent alkyl group, as defined above.C₀-C₄alkylene is a single covalent bond or an alkylene group having from1 to 4 carbon atoms; and C₀-C₆alkylene is a single covalent bond or analkylene group having from 1 to 6 carbon atoms. “Alkenylene” and“Alkynylene” refer to divalent alkenyl and alkynyl groups respsectively,as defined above.

A “cycloalkyl” is a group that comprises one or more saturated and/orpartially saturated rings in which all ring members are carbon, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, andpartially saturated variants of the foregoing, such as cyclohexenyl.Cycloalkyl groups do not comprise an aromatic ring or a heterocyclicring. Certain cycloalkyl groups are C₃-C₈cycloalkyl, in which the groupcontains a single ring with from 3 to 8 ring members. A“(C₃-C₈cycloalkyl)C₀-C₄alkyl” is a C₃-C₈cycloalkyl group linked via asingle covalent bond or a C₁-C₄alkylene group. In certain aspects,C₃₋₆-cycloalkyl groups are substituted one or more times (or preferablybetween one and five times) with substitutents independently selectedfrom a halogen atom, aryl, heteroaryl, trihalomethyl, C₁₋₄-alkoxy orC₁₋₄-alkyl.

Moreover, alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl,etc.) include both “unsubstituted alkyl” and “substituted alkyl”, thelatter of which refers to alkyl moieties having substituents replacing ahydrogen on one or more carbons of the hydrocarbon backbone, which allowthe molecule to perform its intended function.

The term “substituted” is intended to describe moieties havingsubstituents replacing a hydrogen on one or more atoms, e.g. C, O or N,of a molecule. Such substituents can include, for example, oxo, alkyl,alkoxy, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, morpholino,phenol, benzyl, phenyl, piperizine, cyclopentane, cyclohexane, pyridine,5H-tetrazole, triazole, piperidine, or an aromatic or heteroaromaticmoiety, and any combination thereof.

Further examples of substituents of the invention, which are notintended to be limiting, include moieties selected from straight orbranched alkyl (preferably C₁-C₅), cycloalkyl (preferably C₃-C₈), alkoxy(preferably C₁-C₆), thioalkyl (preferably C₁-C₆), alkenyl (preferablyC₂-C₆), alkynyl (preferably C₂-C₆), heterocyclic, carbocyclic, aryl(e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl),aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl,heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group,heteroarylcarbonyl, or heteroaryl group, (CR′R″)₀₋₃NR′R″ (e.g., —NH₂),(CR′R″)₀₋₃CN (e.g., —CN), —NO₂, halogen (e.g., —F, —Cl, —Br, or —I),(CR′R″)₀₋₃C(halogen)₃ (e.g., —CF₃), (CR′R″)₀₋₃CH(halogen)₂,(CR′R″)₀₋₃CH₂(halogen), (CR′R″)₀₋₃CONR′R″, (CR′R″)₀₋₃(CNH)NR′R″,(CR′R″)₀₋₃S(O)₁₋₂NR′R″, (CR′R″)₀₋₃CHO, (CR′R″)₀₋₃O(CR′R″)₀₋₃H,(CR′R″)₀₋₃S(O)₀₋₃R′ (e.g., —SO₃H, —OSO₃H), (CR′R″)₀₋₃O(CR′R″)₀₋₃H (e.g.,—CH₂OCH₃ and —OCH₃), (CR′R″)₀₋₃S(CR′R″)₀₋₃H (e.g., —SH and —SCH₃),(CR′R″)₀₋₃OH (e.g., —OH), (CR′R″)₀₋₃COR′, (CR′R″)₀₋₃ (substituted orunsubstituted phenyl), (CR′R″)₀₋₃(C₃-C₈ cycloalkyl), (CR′R″)₀₋₃CO₂R′(e.g., —CO₂H), or (CR′R″)₀₋₃OR′ group, or the side chain of anynaturally occurring amino acid; wherein R′ and R″ are each independentlyhydrogen, a C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, or aryl group.Such substituents can include, for example, halogen, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, oxime, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety, andany combination thereof. In certain embodiments, a carbonyl moiety (C═O)may be further derivatized with an oxime moiety, e.g., an aldehydemoiety may be derivatized as its oxime (—C═N—OH) analog. It will beunderstood by those skilled in the art that the moieties substituted onthe hydrocarbon chain can themselves be substituted, if appropriate.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “aralkyl” moiety is an alkyl substituted with anaryl (e.g., phenylmethyl (i.e., benzyl)).

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one double bond.

For example, the term “alkenyl” includes straight-chain alkenyl groups(e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl(alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenylgroups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. Theterm alkenyl further includes alkenyl groups that include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain orbranched chain alkenyl group has 6 or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from 3-8 carbon atoms in their ringstructure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

Moreover, the term alkenyl includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond.

For example, the term “alkynyl” includes straight-chain alkynyl groups(e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkylor cycloalkenyl substituted alkynyl groups. The term alkynyl furtherincludes alkynyl groups that include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “amine” or “amino” should be understood as being broadlyapplied to both a molecule, or a moiety or functional group, asgenerally understood in the art, and may be primary, secondary, ortertiary. The term “amine” or “amino” includes compounds where anitrogen atom is covalently bonded to at least one carbon, hydrogen orheteroatom. The terms include, for example, but are not limited to,“alkylamino,” “arylamino,” “diarylamino,” “alkylarylamino,”“alkylaminoaryl,” “arylaminoalkyl,” “alkaminoalkyl,” “amide,” “amido,”and “aminocarbonyl.” The term “alkyl amino” comprises groups andcompounds wherein the nitrogen is bound to at least one additional alkylgroup. The term “dialkyl amino” includes groups wherein the nitrogenatom is bound to at least two additional alkyl groups. The term“arylamino” and “diarylamino” include groups wherein the nitrogen isbound to at least one or two aryl groups, respectively. The term“alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, oralkynyl group bound to a nitrogen atom which is also bound to an alkylgroup.

The term “amide,” “amido” or “aminocarbonyl” includes compounds ormoieties which contain a nitrogen atom which is bound to the carbon of acarbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl”or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl oralkynyl groups bound to an amino group bound to a carbonyl group. Itincludes arylaminocarbonyl and arylcarbonylamino groups which includearyl or heteroaryl moieties bound to an amino group which is bound tothe carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,”“arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,”“alkynylcarbonylamino,” and “arylcarbonylamino” are included in term“amide.” Amides also include urea groups (aminocarbonylamino) andcarbamates (oxycarbonylamino)

The term “aryl” includes groups, including 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole,imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine,pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, theterm “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic,e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole,benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,isoquinoline, anthryl, phenanthryl, napthridine, indole, benzofuran,purine, benzofuran, deazapurine, or indolizine. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics.” Thearomatic ring can be substituted at one or more ring positions with suchsubstituents as described above, as for example, alkyl, halogen,hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a polycycle (e.g., tetralin).

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 5- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

The term “acyl” includes compounds and moieties which contain the acylradical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups and may include cyclic groups such as cyclopentoxy.Examples of substituted alkoxy groups include halogenated alkoxy groups.The alkoxy groups can be substituted with groups such as alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of moieties that contain a carbonylinclude aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc. The term “carboxy moiety” or “carbonyl moiety” refersto groups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties, (wherein a nitrogen atom is boundto the carbon of the carbonyl group, e.g., an amide), aminocarbonyloxymoieties, wherein an oxygen and a nitrogen atom are both bond to thecarbon of the carbonyl group (e.g., also referred to as a “carbamate”).Furthermore, aminocarbonylamino groups (e.g., ureas) are also include aswell as other combinations of carbonyl groups bound to heteroatoms(e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms).Furthermore, the heteroatom can be further substituted with one or morealkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.The term “thiocarbonyl moiety” includes moieties that are analogous tocarbonyl moieties. For example, “thiocarbonyl” moieties includeaminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include,oxythiocarbonyls (oxygen bound to the carbon atom),aminothiocarbonylamino groups, etc.

The term “ether” includes compounds or moieties that contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom that is covalentlybonded to another alkyl group.

The term “ester” includes compounds and moieties that contain a carbonor a heteroatom bound to an oxygen atom that is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom that is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The terms “polycyclyl” or “polycyclic radical” include moieties with twoor more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

Additionally, the phrase “any combination thereof” implies that anynumber of the listed functional groups and molecules may be combined tocreate a larger molecular architecture. For example, the terms “phenyl,”“carbonyl” (or “=0”), “—O—,” “—OH,” and C₁₋₆ (i.e., —CH₃ and—CH₂CH₂CH₂—) can be combined to form a 3-methoxy-4-propoxybenzoic acidsubstituent. It is to be understood that when combining functionalgroups and molecules to create a larger molecular architecture,hydrogens can be removed or added, as required to satisfy the valence ofeach atom.

It is to be understood that all of the compounds of the inventiondescribed above will further include bonds between adjacent atoms and/orhydrogens as required to satisfy the valence of each atom. That is,bonds and/or hydrogen atoms are added to provide the following number oftotal bonds to each of the following types of atoms: carbon: four bonds;nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds.

It will be noted that the structures of some of the compounds of thisinvention include asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers, stereoisomers, rotamers, tautomers, diastereomers, orracemates) are included within the scope of this invention. Such isomerscan be obtained in substantially pure form by classical separationtechniques and by stereochemically controlled synthesis. Furthermore,the structures and other compounds and moieties discussed in thisapplication also include all tautomers thereof. Compounds describedherein may be obtained through art recognized synthesis strategies.

It will also be noted that the substituents of some of the compounds ofthis invention include isomeric cyclic structures. It is to beunderstood accordingly that constitutional isomers of particularsubstituents are included within the scope of this invention, unlessindicated otherwise. For example, the term “tetrazole” includestetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole.

Use in Bacterial Infection

The compounds of the present invention have valuable pharmacologicalproperties and are useful in the treatment of diseases. In certainembodiments, compounds of the invention are useful in the treatment ofbacterial infections.

The term “use” includes any one or more of the following embodiments ofthe invention, respectively: the use in the treatment of bacterialinfections; the use for the manufacture of pharmaceutical compositionsfor use in the treatment of these diseases, e.g., in the manufacture ofa medicament; methods of use of compounds of the invention in thetreatment of these diseases; pharmaceutical preparations havingcompounds of the invention for the treatment of these diseases; andcompounds of the invention for use in the treatment of these diseases;as appropriate and expedient, if not stated otherwise. In particular,diseases to be treated and are thus preferred for use of a compound ofthe present invention are selected from bacterial infections, as well asthose diseases that depend on the activity of EF-Tu. The term “use”further includes embodiments of compositions herein which bind to anEF-Tu protein sufficiently to serve as tracers or labels, so that whencoupled to a fluor or tag, or made radioactive, can be used as aresearch reagent or as a diagnostic or an imaging agent.

In certain embodiments, a compound of the present invention is used fortreating EF-Tu-associated diseases, and use of the compound of thepresent invention as an inhibitor of any one or more EF-Tu proteins. Itis envisioned that a use can be a treatment of inhibiting one or moreisoforms of EF-Tu.

Assays

The inhibition of antibacterial activity by the compounds of theinvention may be measured using a number of assays available in the art.An example of such an assay is the standard minimum inhibitoryconcentration (MIC) test conducted according to CSLI guidelines.

Pharmaceutical Compositions

The language “effective amount” of the compound is that amount necessaryor sufficient to treat or prevent a bacterial infection, e.g. preventthe various morphological and somatic symptoms of a bacterial infection,and/or a disease or condition described herein. In an example, aneffective amount of the compound of the invention is the amountsufficient to treat a bacterial infection in a subject. The effectiveamount can vary depending on such factors as the size and weight of thesubject, the type of illness, or the particular compound of theinvention. For example, the choice of the compound of the invention canaffect what constitutes an “effective amount.” One of ordinary skill inthe art would be able to study the factors contained herein and make thedetermination regarding the effective amount of the compounds of theinvention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of a bacterial infection. Further,several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of thecompound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Compounds of the invention may be used in the treatment of states,disorders or diseases as described herein, or for the manufacture ofpharmaceutical compositions for use in the treatment of these diseases.Methods of use of compounds of the present invention in the treatment ofthese diseases, or pharmaceutical preparations having compounds of thepresent invention for the treatment of these diseases.

The language “pharmaceutical composition” includes preparations suitablefor administration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, α-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteraladministration. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient that can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound that produces a therapeutic effect. Generally,out of one hundred percent, this amount will range from about 1 percentto about ninety-nine percent of active ingredient, preferably from about5 percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluent commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc., administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral and/or IV administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous and subcutaneousdoses of the compounds of this invention for a patient, when used forthe indicated analgesic effects, will range from about 0.0001 to about100 mg per kilogram of body weight per day, more preferably from about0.01 to about 50 mg per kg per day, and still more preferably from about1.0 to about 100 mg per kg per day. An effective amount is that amounttreats a bacterial infection.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

Synthetic Procedure

Compounds of the present invention are prepared from commonly availablecompounds using procedures known to those skilled in the art, includingany one or more of the following conditions without limitation:

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group,” unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such ase.g., Science of Synthesis: Houben-Weyl Methods of MolecularTransformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp.(URL: http://www.science-of-synthesis.com (Electronic Version, 48Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.Meienhofer), Academic Press, London and New York 1981, in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosäuren, Peptide, Proteine” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideand Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e., without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g., by enzymatic cleavage).

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g., the sodium salt of 2-ethylhexanoic acid, with organicalkali metal or alkaline earth metal compounds, such as thecorresponding hydroxides, carbonates or hydrogen carbonates, such assodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g., by treatingthe compounds with an acid or a suitable anion exchange reagent.Internal salts of compounds of the present invention containing acid andbasic salt-forming groups, e.g., a free carboxy group and a free aminogroup, may be formed, e.g., by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g., with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by, e.g., medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g., using chromatographic methods,distribution methods, (re-) crystallization, and the like.

General Process Conditions

The following applies in general to all processes mentioned throughoutthis disclosure.

The process steps to synthesize the compounds of the invention can becarried out under reaction conditions that are known per se, includingthose mentioned specifically, in the absence or, customarily, in thepresence of solvents or diluents, including, for example, solvents ordiluents that are inert towards the reagents used and dissolve them, inthe absence or presence of catalysts, condensation or neutralizingagents, for example ion exchangers, such as cation exchangers, e.g., inthe H⁺ form, depending on the nature of the reaction and/or of thereactants at reduced, normal or elevated temperature, for example in atemperature range of from about −100° C. to about 190° C., including,for example, from approximately −80° C. to approximately 150° C., forexample at from −80 to −60° C., at room temperature, at from −20 to 40°C. or at reflux temperature, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example under an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described in Science of Synthesis: Houben-Weyl Methods ofMolecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

Prodrugs

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the compounds ofthe invention. For example, compounds of the invention having freeamino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the invention.The amino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Any reference to a compound of the present invention is therefore to beunderstood as referring also to the corresponding pro-drugs of thecompound of the present invention, as appropriate and expedient.

Combinations

A compound of the present invention may also be used in combination withother agents, e.g., an additional antibacterial compound that is or isnot a compound of the invention, for treatment of a bacterial infectionin a subject.

By the term “combination” is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound of the present invention and a combination partner maybe administered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g., synergistic, effect, or any combination thereof.

A compound of the present invention may be used in combination withanother antibacterial agent. The term “antibacterial agent” refers toany substance that is either bactericidal or bacteriostatic, i.e.,capable of killing or inhibiting the growth of bacterial cells.Antibacterial agents include antibiotics, biocides, antimicrobials, andbacteriostatic agents. The known types of antibiotics include, e.g.,cell wall synthesis inhibitors, cell membrane inhibitors, proteinsynthesis inhibitors and inhibitors that bind to or affect the synthesisof DNA or RNA. Numerous antibiotic agents suitable for use in thetreatment of bacteria-related diseases and disorders, are known anddisclosed, e.g. in The Physician's Desk Reference (PDR), MedicalEconomics Company (Montvale, N.J.), (53.sup.rd Ed.), 1999; Mayo MedicalCenter Formulary, Unabridged Version, Mayo Clinic (Rochester, Minn.),January 1998; Merck Index: An Encyclopedia of Chemicals, Drugs andBiologicals, (11.sup.th Ed.), Merck & Co., Inc. (Rahway, N.J.), 1989;University of Wisconsin Antimicrobial Use Guide,http://www.medsch.wisc.edu/clinsci/5amcg/amcg.html; Introduction on theUse of the Antibiotics Guideline, of Specific Antibiotic Classes, ThomasJefferson University,http://jeffiine.tju.edu/CWIS/OAC/antibiotics_guide/intro.html; andreferences cited therein.

Examples of antibiotics for use in combination with the compounds of theinvention include, but are not limited to, quinolone, macrolide,glycopeptide, oxazolidinone, β-lactams (including amoxicillin,ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, methicillin, mezlocillin, nafcillin, oxacillin,penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam,ticarcillin, sulbactam, tazobactam, clavulanate), cephalosporins(cefaclor, cefadroxil, cefamandole, cefazolin, cefdinir, cefditoren,cefepime, cefixime, cefonicid, cefoperazone, cefotaxime, cefotetan,cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, cephalexin, cephalothin, cephapirin,cephradine), aminoglycosides (including gentamycin, streptomycin,amikacin, kanamycin, viomycin, capreomycin), ethionamide, prothionamide,cycloserine, dapsone, clofazimine, tetracyclines (tetracycline,doxycycline, chlortetracycline, oxytetracycline, minocyclinedemeclocycline), oxazolidinones (linezolid, eperezolid), metronidazole,rifabutin, isoniazonid, ethambutol, and combinations thereof.

Examples of anti-viral agents for use in combination with the compoundsof the invention include, but are not limited to, zidovudine,lamivudine, didanosine, zalcitabine, stavudine, abacavir, nevirapine,delavirdine, emtricitabine, efavirenz, saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, tenofovir, adefovir, atazanavir, fosamprenavir,hydroxyurea, AL-721, ampligen, butylated hydroxytoluene;polymannoacetate, castanospermine; contracan; creme pharmatex, CS-87,penciclovir, famciclovir, acyclovir, cytofovir, ganciclovir, dextransulfate, D-penicillamine trisodium phosphonoformate, fusidic acid,HPA-23, eflornithine, nonoxynol, pentamidine isethionate, peptide T,phenyloin, isoniazid, ribavirin, rifabutin, ansamycin, trimetrexate,SK-818, suramin, UA001, enfuvirtide, gp41-derived peptides, antibodiesto CD4, soluble CD4, CD4-containing molecules, CD4-IgG2, andcombinations thereof.

Further examples of agents the compounds of the present invention can beused in combination with include, but are not limited to, free radicalscavengers, ascorbic acid, Vitamin C, anti-cancer agents,chemotherapeutic agents, non-steroidal anti-inflammatory drugs,steroidal anti-inflammatory drugs, anti-fungal agents, detoxifyingagents, analgesics, bronchodilators, drugs for the treatment of vascularischemia anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics, immunosuppressants, lymphokynes,α-and-β-interferon and combinations thereof.

The compound of the invention and any additional agent may be formulatedin separate dosage forms. Alternatively, to decrease the number ofdosage forms administered to a patient, the compound of the inventionand any additional agent may be formulated together in any combination.For example, the compound of the invention inhibitor may be formulatedin one dosage form and the additional agent may be formulated togetherin another dosage form. Any separate dosage forms may be administered atthe same time or different times.

Alternatively, a composition of this invention comprises an additionalagent as described herein. Each component may be present in individualcompositions, combination compositions, or in a single composition.

Exemplification of the Invention

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The practice of the presentinvention will employ, unless otherwise indicated, conventionaltechniques of cell biology, cell culture, molecular biology, transgenicbiology, microbiology and immunology, which are within the skill of theart.

General Synthesis Methods

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

EXAMPLES Definitions

-   A, Å Ankstrom-   ACN acetonitrile-   AcOH acetic acid-   aq aqueous-   bnBr benzylbromide-   boc tert-butoxycarbonyl-   C Celsius-   cat. catalytic-   CDI cabonyldiimidazole-   CSA camphorsulfonic acid-   conc. concentrated-   C₂CO₃ cesium carbonate-   Da Daltons-   deg degrees-   DIBAL, DIBAL-H diisobutylaluminum hydride-   DIPEA diisopropylethylamine-   DIPC N,N′-diisopropylcarbodiimide-   DMF N,N-dimethylformamide-   DMI 1,3 dimethyl-2-imidazolidinone-   DMP Dess-Martin periodinane-   DCC N,N-dicyclohexylcarbodiimide-   DCE dichloroethane-   DCM dichloromethane-   DMAP 4-dimethylaminopyridine-   DMSO dimethylsulfoxide-   EtOAc ethyl acetate-   EtOH ethanol-   eq equivalents-   g gas-   Grubbs II    1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophenylmethylene)(tricyclohexyl    phosphine)ruthenium-   h hours-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HMPA hexamethlphosphoramide-   hep heptane-   HCl hydrochloric acid-   inh. inhibition-   imid. Imidazole-   K Kelvin-   KHMDS potassium hexamethyldisilylazide-   K₂CO₃ potassium carbonate-   LDA lithiumdiisopropylamine-   LiBH₄ lithium borohydride-   LHMDS lithiumhexamethyldisilylazide-   LC liquid chromatography-   LC/MS liquid chromatography mass spectrum-   M molar-   MeCN acetonitrile-   MeOH methanol-   MgSO₄ magnesium sulfate-   MHz megahertz-   min minutes-   mol. sieves molecular sieves-   NaBH₄ sodium borohydride-   N normal-   NMR nuclear magnetic resonance-   Pd/C palladium on carbon-   PEG(750) O-(2-aminoethyl)-O′-methyl polyethylene glycol 750;    NH₂(CH₂CH₂O)_(n)CH₃; CAS#[80506-64-5]; Fluka 07964; AVERAGE MW=750-   PS polystyrene-   Py pyridine-   PPM parts per million-   RP reverse phase-   RT room temperature-   R_(t) retention time-   s solid-   sat. saturated-   TBS tert-butyldimethylsilyl-   TMS trimethylsilyl-   TBAF tetrabutylammonum fluoride-   TBTU O-benzotriazol-1-yl-N,N, N,N′-tetramethyluronium    tetrafluoroborate-   TLC thin-layer chromatography-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   h hours-   min minutes-   m/z mass to charge-   MS mass spectrum-   HRMS high resolution mass spectrum-   NMR nuclear magnetic resonance

Analytical Methods

NMR: proton spectra are recorded on a Bruker 400 MHz ultrashieldspectrometer unless otherwise noted. Chemical shifts are reported in ppmrelative to methanol (δ 3.31), dimethyl sulfoxide (δ 2.50), orchloroform (δ 7.26).

LC/MS:

Method 1: compounds are analyzed on an Inertsil ODS-3 column (C18,50×4.6 mm, 3 μm) with a 2 min gradient elution (20-80%acetonitrile/H₂O/5 mM ammonium formate) and a flow rate of 4 mL/min.Method 5: GENERAL LC/MS method with acid mobile phase (0.1% formic acid)and fast gradient. Electrospray mass spectra (+) and (−), DAD-UVchromatogram 200-400 nm, scan range 120-1500 Da. Gradient: 20-80%MeCN/H₂O in 2 min (2 mL/min), 2 μL injection. Column: Inertsil ODS3C-18, 3 cm×33 mm×3.0 μm, 40 deg C.Method 6: GENERAL LC/MS method with neutral mobile phase (5 mM NH₄⁺HCOO⁻) and fast (20-80%) gradient. Electrospray mass spectra (+) and(−), DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da. Gradient:20-80% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection. Column. InertsilODS3 C-18, 3 cm×33 mm×3.0 μm, 40 deg C.Method 7: LC/MS method for NON-POLAR (greasy) compounds with acid mobilephase (0.1% formic acid) and fast (40-90%) gradient. Electrospray massspectra (+) and (−), DAD-UV chromatogram 200-400 nm, scan range 120-1500Da. Gradient: 40-90% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection.Column. Inertsil C8-3, 3 cm×33 mm×3.0 μm, 40 deg C.Method 8: LC/MS method for NON-POLAR (greasy) compounds with neutralmobile phase (5 mM NH₄ ⁺HCOO⁻) and fast (40-90%) gradient. Electrospraymass spectra (+) and (−), DAD-UV chromatogram 200-400 nm, scan range120-1500 Da. Gradient: 40-90% MeCN/H₂O in 2 min (2 mL/min), 2 μLinjection. Column: Inertsil C8-3, 3.0 cm×33 mm×3.0 μm, 40 deg C.Method 9: LC/MS method with broad range (5-95%) gradient with acidmobile phase (0.1% Formic Acid). Electrospray mass spectra (+) and (−),DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da. Gradient: 5-95%MeCN/H₂O in 2 min (2 mL/min), 2 μL injection. Column: Inertsil C8-3, 3.0cm×33 mm×3.0 μm, 40 deg C.Method 10: LC/MS method with broad range (5-95%) gradient with neutralmobile phase (5 mM NH₄ ⁺HCOO⁻). Electrospray mass spectra (+) and (−),DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da. Gradient: 5-95%MeCN/H₂O in 2 min (2 mL/min), 2 μL injection. Column: Inertsil C8-3, 3cm×433 mm×3.0 μm, 40 deg C.Method 11: LC/MS method for POLAR compounds with acid mobile phase (0.1%formic acid) and slow (0-100%) gradient. Electrospray mass spectra (+)and (−), DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da.Gradient: 0-100% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection. Column:Inertsil ODS3 (C-18, 3 cm×33 mm×3.0 μm, 40 degree C.)Method 12: LC/MS method for POLAR compounds with neutral mobile phase (5mM NH₄ ⁺HCOO⁻) and slow (0-100%) gradient. Electrospray mass spectra (+)and (−), DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da.Gradient: 0-100% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection. Column:Inertsil ODS-3 (C-18, 3 cm×33 mm×3.0 μm, 40 deg C.Method 13: Compounds are analyzed on an Inertsil ODS-3 column (C8, 30mm×3.0 mm, 3.0 um) with a 2 min gradient elution (5-90%acetonitrile/H₂O/5 mM ammonium formate) and a flow rate of 2 mL/min.Method 14: Compounds are analyzed on an Inertsil ODS-3 column (C8, 30mm×3.0 mm, 3.0 um) with a 2 min gradient elution (5-90%acetonitrile/H₂O/0.1% formic acid) and a flow rate of 2 mL/min.HPLC purification utilizes a C8 or C18 column (30×100 mm, 5 um, brand:Sunfire or XTerra) and is performed with an appropriate gradient usingtwo methods (unless otherwise noted). Method 1 consists of 0.1% TFA in5%-95% ACN in H₂O. Method 2 consists of 10 mM NH₄OH in 5%-95% ACN inH₂O.LC analysis utilizes a liquid chromatography-UV detection (LC-UV) usinga Agilent 1100 liquid chromatograph. LC conditions are as follows:column: Atlantis C18 (Waters, Inc.), 15 cm×4.6 mm×5 μm; columntemperature: ambient; flow rate: 1.4 mL/min; injection volume: 3.0 μL;gradient: A=0.1% trifluoroacetic acid (TFA) in water, B=0.05%trifluoroacetic Acid (TFA) in acetonitrile, 0-95% B in 19.0 min, 1.8 minhold.

The compound of general formula (I) may be prepared via syntheticmethods well known to those skilled in the art, or alternativelyisolated from a fermentation broth. See, for example, U.S. Pat. No.5,202,241. The compound of general structural formula (II) may beprepared by process A by the acid or base mediated rearrangement ofcompound (i) in the presence of water and a suitable acid or base. Thecompound of general formula (iii) may be prepared in process B from (ii)directly via reaction with azide or alternatively through a multi stepprocess which includes removal of the ester functionality throughhydrolysis with a suitable base or acid, activation of the carboxylicacid moiety using a suitable activation agent, and reaction with asuitable reagent such as azide. Azides represented by formula (iii) areknown in the art and are readily synthesized by standard procedurescommonly employed in the art. The compound of general formula (Iv) maybe prepared by reaction of the azide (iii) with a nucleophile, alcohol,amine, or protecting group (X₁). A suitable protecting group can beselected by those skilled in the art. Protecting groups are selected sothat they are suitable for the depicted transformations and can beremoved following the synthesis with little or no loss of yield. Theintroduction and selective removal of protecting groups are taught inGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &Sons (1991). The compound of general structural formula (v) may beprepared by reacting compound (iv) with a reactive reagent such as anelectrophile, alkylating agent, acylating agent, or protecting group(X₂) to afford compound (v). The compound of general structure (vi) canbe prepared by reacting compound (v) with acid, base, a nucleophile, orelectrophile to remove the protecting group (X₁). The compound ofgeneral structure (vii) can be prepared by reacting compound (vi) with asuitable electrophile, alkylating agent, or acylating agent (X₃). Thecompound of general structure (viii) can be prepared by reactingcompound (vii) with a suitable electrophile, alkylating agent, oracylating agent (X₄). The compound of general structure (ix) can beprepared by reacting compound (viii) with acid, base, a nucleophile, orelectrophile to remove any remaining protecting groups. Alternatively,any of these steps (A-H) may be performed in a different order, or withsome steps removed or slightly altered, which is obvious to thoseskilled in the art.

Intermediate vi can also be cyclized to form a heterocycle orheteroaromatic ring according to process J through an alkylation,acyation, cyclization, transition metal-mediated coupling, orcondensation which may be acid or base catalyzed to form x. Compound xcan be further derivitized through alkylation, acylation, transitionmetal-mediated coupling, etc. and the protecting groups removed throughprocess K to provide xi.

Example 1 Preparation of Diacid 3 of Table A

Steps 1-3:

To a solution of XII (3.1 g, 2.4 mmol) in (CH₃)₂CO (350 mL) and H₂O (40mL), is added NaOH crystals (0.192 g, 4.8 mmol). The reaction mixture issonicated and stirred at 22° C. for 1 hour (LC/MS: m/z [M+H]⁺ 1125,R_(t)=1.12 min, method 1). The reaction mixture is then cooled to 0° C.and EtOCOCl (17.8 mL, 192 mmol) is added via syringe. After stirringreaction mixture at 0° C. for 1.5 hours, the reaction shows the acylcarbonate intermediate (MS m/z 1197 [M+H]⁺). NaN₃ solid (6.3 g, 96 mmol)is added to the reaction mixture and is stirred at 22° C. for 12 hours.15 g of SiO₂ is added and all solvents are evaporated in vacuo. Thesolid is purified by flash chromatography, eluting with 100% EtOAc toprovide 3.4 g (quant yield), of a cream solid, XIII. MS m/z 1167(M+H₂O).

Step 4:

To a solution of the acid sodium salt (8 g, 63 mmol) in DMF (100 mL) isadded MeI (7.9 mL, 126 mmol) and reaction mixture is stirred for 5 daysat 22° C. The excess solvents are removed under reduced pressure. Theresidue is diluted with EtOAc and washed with aqueous brine solution.The organic layers are combined and dried over Na₂SO₄, filtered andconcentrated to provide 6.2 g (83%) of a yellow oil, 4-hydroxy-butyricacid methyl ester.

Step 5:

To a solution of XIII (3 g, 2.6 mmol) in PhMe (100 mL) is added4-hydroxy-butyric acid methyl ester (1.2 g, 10.4 mmol) and the reactionmixture is stirred at 75° C. for 12 hours. 7 g of SiO₂ is added to themix and the solvents are concentrated under reduced pressure. The solidis purified by flash chromatography, eluting with 100% EtOAc to provide3.82 g (quant. yield), of a yellow solid, XIV. MS m/z 1240 (M+H)⁺.

Step 6:

To a solution of XIV (1.8 g, 0.15 mmol) in DMF (50 mL), is added4-bromo-butyric acid methyl ester (1 g, 0.87 mmol) and Cs₂CO₃ (800 mg,0.48 mmol). The reaction is stirred at 22° C. for 48 hours. 5 g SiO₂ isadded and all solvents are evaporated in vacuo. The solid is purified byflash chromatography, eluting with MeOH/DCM (0-10%) to provide 1.5 g(75%), of a yellow solid. MS m/z 1357 (M+H₂O).

Step 7:

To a solution of the diester (250 mg, 0.187 mmol) in MeOH (10 mL) andH₂O (2 mL) is added NaOH crystals (37 mg, 0.933 mmol) and the reactionmixture is stirred for 72 hours at 22° C. 6 g of SiO₂ is added and thesolvents are concentrated under reduced pressure. The solid is purifiedby flash chromatography, eluting with MeOH/DCM (5-10%) then to 10%MeOH/DCM with 1% AcOH to provide 0.2 g of a yellow oil. The yellow oilis purified by Gilson HPLC eluting with ACN/H₂O (5-50%) with 3%n-propanol. Lypholization for 12 h provides 4 mg (16%) of a white solid,3. LC/MS: m/z 1329 [M+H₂O]⁺, method 1. LC: R_(t)=8.84 min, HRMS (ES⁺)C₅₆H₅₇N₁₃O₁₃S₆: Calc.: 1312.2601 [M+H]⁺; Found: 1312.2637. ¹H NMR(DMSO-d6, 600 MHz, 300 K) δ 9.047 (d, 1H), 8.698 (d, 1H), 8.683 (d, 1H),8.605 (s, 1H), 8.459 (dd, 1H), 8.381 (d, 1H), 8.265 (s, 1H), 8.238 (d,1H), 7.758 (s, 1H), 7.388 (m, 1H), 7.361 (s, 1H), 7.321 (m, 1H), 7.289(m, 1H), 7.239 (m, 1H), 6.06 (b, 1H), 5.295 (m, 1H), 5.237 (t, 1H),5.211 (dd, 1H), 4.998 (d, 1H), 4.979 (s, 2H), 4.272-3.787 (dd, 2H),4.163 (t, 2H), 4.007 (b, 2H), 3.391 (s, 3H), 2.717-1.298 (dd, 2H), 2.589(s, 3H), 2.479 (d, 3H), 2.336 (t, 2H), 2.303 (t, 2H), 2.169 (m, 1H),1.900 (m, 2H), 1.878 (m, 2H), 0.881-0.846 (d, 3H).

Example 2 Preparation of Diacid 4 of Table A

Step 1:

To a suspension of acylazide (XIII, 0.600 g, 0.522 mmol) in toluene (20mL) is added trans-4-hydroxy-cyclohexane carboxylic acid ethyl ester(0.134 g, 0.778 mmol) and the mixture is stirred at 80° C. for 5 h. Thereaction is concentrated in vacuo and the crude product is purified byflash chromatography (MeOH/DCM) to yield 0.236 g (0.182 mmol, 35%) ofthe ester.

Step 2:

To a solution of the ester (125 mg, 0.098 mmol) in DMF (0.8 mL), isadded methyl 4-bromobutyrate (67 uL, 0.588 mmol) and Cs₂CO₃ (112 mg,0.341 mmol). The reaction is stirred at rt for 18 hours. The reactionmixture is concentrated, and the residue is purified by flashchromatography, eluting with MeOH/DCM (0-10%) to provide 100 mg (74.2%),of a yellow solid, the diester. MS, m/z 1381 (M+H)⁺.

Step 3:

To a solution of the diester (180 mg, 0.130 mmol) in MeOH (3.6 mL) andTHF (0.9 mL) is added 3 N NaOH (0.45 mL, 1.30 mmol) and the reactionmixture is stirred for 7 hours at rt. The reaction mixture isneutralized with solid NH₄Cl (70 mg, 1.30 mmol). The mixture is thenconcentrated under reduced pressure. The yellow solid is purified byGilson HPLC eluting with ACN/H₂O with 0.1% TFA (gradient elution:30-80%). Lyophylization for 12 h provides 54 mg of light yellow solid,4. LC: R_(t)=11.68 min; HRMS (ES⁺) C₅₉H₆₁N₁₃O₁₃S₆: Calc.: 1352.2914[M+H]⁺; Found: 1352.2878.

Example 3 Preparation of Diacid 5 of Table A

Step 1:

To a solution of the cyclohexyl ester (Example 2, step 1, 300 mg, 0.234mmol) in DMF (2.1 mL), is added ethyl 7-bromo-heptanoate (282 uL, 1.40mmol) and Cs₂CO₃ (267 mg, 0.819 mmol). The reaction is stirred at rt for18 hours. The reaction mixture is concentrated, and the residue ispurified by flash chromatography, eluting with MeOH/DCM (0-10%) toprovide 210 mg of diester. MS m/z 1437 (M+H)⁺.

Step 2:

To a solution of the diester (210 mg, 0.146 mmol) in MeOH (4.5 mL) andTHF (1.5 mL) is added 3N NaOH (0.49 mL, 1.46 mmol) and the reactionmixture is stirred for 18 hours at rt. The reaction mixture isneutralized with solid NH₄Cl (81 mg, 1.50 mmol), and is concentratedunder reduced pressure. The yellow solid is purified by Gilson HPLCeluting with ACN/H₂O with 0.1% TFA (30-80%). Lyophylization for 12 hprovides 86 mg of light yellow solid, 5. LC: R_(t)=12.82 min, HRMS (ES⁺)C₆₂H₆₇N₁₃O₁₃S₆: Calc.:1394.3384 [M+H]⁺; Found: 1394.3356.

Example 4 Preparation of Diacid 6 of Table A

Compound 6 is prepared according to example 1 and scheme 3.

Step 1:

To a solution of XIII (1 g, 0.87 mmol) in dioxane (80 mL) is addedtrans-4-hydroxy cyclohexane carboxylic acid methyl ester (0.46 g, 2.9mmol) and the reaction mixture is stirred at 80° C. for 4 h. SiO₂ isadded to the mix and the solvents are concentrated under reducedpressure. The solid is purified by flash chromatography, eluting with10% DCM/MeOH to provide 530 mg (47.7% yield), of a yellow solid, theurethane. MS m/z 1280 (M+H)⁺.

Step 2:

To a solution of the urethane (300 mg, 0.234 mmol) and Cs₂CO₃ (267 mg,0.820 mmol) in DMF (2 mL), is added methyl 5-bromovalerate (0.20 mL,1.404 mmol). The reaction is stirred at rt for 12 h, filtered andconcentrated. The residue is purified by flash chromatography, elutingwith MeOH/DCM (gradient: 0-10%) to provide 270 mg (82.5%), of a yellowsolid. MS m/z 1395 (M+H)⁺.

Step 3:

To a solution of the diester (270 mg, 0.194 mmol) in MeOH (6.5 mL) andTHF (2.5 mL) is added 3 N NaOH (0.65 mg, 1.94 mmol) and the reactionmixture is stirred for 12 h at rt. The reaction is neutralized withNH₄Cl until pH=6-7. The reaction is concentrated under vacuum. Theresidue is dissolved in DMF/H₂O, purified with HPLC (gradient elutionMeCN/H₂O, 0.1% TFA modifier), and lypholized for 12 h to provide 98.5 mg(37.2%) of a light yellow solid, 6. HRMS (ES⁺) C₆₀H₆₃N₁₃O₁₃S₆: Calc.:1366.3071 [M+H]⁺; Found: 1366.3009. LC/MS: m/z [M+2H]⁺ 1367, R_(t)=1.41min (method 14). ¹H NMR: (600 MHz, DMSO-d6) δ 9.132 (d, 1H), 8.707 (d,1H), 8.681 (d, 1H), 8.604 (s, 1H), 8.465 (dd, 1H), 8.387 (d, 1H), 8.257(s, 1H), 8.217 (d, 1H), 7.713 (s, 1H), 7.394 (m, 1H), 7.354 (s, 1H),7.322 (d, 2H), 7.285 (t, 2H), 7.235 (t, 1H), 6.175 (b, 1H), 5.294 (m,1H), 5.239 (t, 1H), 5.213 (dd, 1H), 5.007 (d, 1H), 4.983 (d, 2H), 4.666(m, 1H), 4.287-3.796 (dd, 2H), 3.982 (b, 2H), 3.392 (s, 3H), 2.794-1.285(dd, 2H), 2.592 (s, 3H), 2.479 (d, 3H), 2.277 (t, 2H), 2.256 (m, 1H),2.170 (m, 1H), 2.010-1.476 (m, 4H), 1.931-1.476 (m, 4H), 1.686 (m, 2H),1.575 (m, 2H), 0.885 (d, 3H), 0.848 (d, 3H).

Example 5 Preparation of Diacid 7 of Table A

Compound 7 is prepared according to the procedures described in example2. LC/MS: m/z [M+2H]⁺ 1381, R_(t)=1.43 min (method 14).

Example 6 Preparation of Diacid 8 of Table A

Compound 8 is prepared according to the procedures described in example8. LC/MS: m/z [M+H]⁺ 1310, R_(t)=1.2 min (method 5). ¹H NMR (DMSO-d6,400 MHz) δ ppm 0.78-0.94 (m, 6H) 1.22-1.32 (br, 1H), 1.40-1.60 (br, 4H),1.70-1.85 (br, 2H), 2.10-2.37 (m, 7H), 2.48 (s, 3H), 2.59 (s, 3H),2.65-2.78 (m, 1H), 3.39 (s, 3H), 3.69-3.85 (m, 3H), 4.21-4.35 (m, 1H),4.96-5.03 (br, 3H), 5.17-5.35 (m, 3H), 6.00-6.12 (br, 1H), 7.22-7.44 (m,7H), 7.96 (s, 1H), 8.20-8.31 (m, 2H), 8.36-8.43 (m, 1H), 8.43-8.51 (m,1H), 8.61 (s, 1H), 8.64-8.76 (m, 2H), 9.05 (d, J=7.71 Hz, 1H),11.87-12.22 (br, 2H).

Example 7 Preparation of Diacid 9 of Table A

Compound 9 is prepared according to the procedures described in example2. LC/MS: m/z [M+H]⁺ 1338, R_(t)=1.3 (method 5).

Example 8 Preparation of Diacid 10 of Table A

Step 1:

A suspension of acyl-azide (XIII, 920 mg) is heated (80° C.) in t-BuOH(100 g). After 2 h complete dissolution occurrs and after 12 h thereaction appears complete by LC/MS. The solution is concentrateddirectly onto SiO₂ and chromatographed (gradient elution: 50-70%EtOAc/hexanes) which affords 600 mg of the boc-amine, a white solid.LC/MS: m/z [M+H]⁺ 1196, R_(t)=1.72 min, (method 1).

Step 2:

To a solution of the boc-amine (540 mg, 0.451 mmol) in DCM (250 mL) isadded acetic anhydride (0.100 mL, 0.979 mmol), pyridine (1.0 mL, 12.4mmol) and DMAP (20 mg, 0.169 mmol). The reaction is stirred for 3 h,concentrated directly onto SiO₂ and chromatographed (gradient elution:50-70% EtOAc/hexanes) which provides 465 mg of boc-amine-acetate. LC/MS(method 1): R_(t)=1.81 min, [M+H]⁺ 1238.

Step 3:

To a solution of the boc-amine-acetate (1 g, 0.836 mmol) in DMF (10 mL)is added cesium carbonate (>10 fold excess). The reaction is stirred for12 h and concentrated onto SiO₂. The crude material is purified by flashcolumn chromatography (gradient elution: 0-10% MeOH in DCM) to afford700 mg of the alkylated product (with the acetate removed).

Step 4:

To a solution of the alkylated boc-amine (100 mg, 0.076 mmol) in DCM (15mL) is added HCl (g) via a stream. After 10 min, the reaction appearedcomplete by LC/MS and the reaction is concentrated 3× from DCM.

Step 5-6:

To a solution of the amine salt in DCM (15 mL) is added excess TBTU (>10equivalents) 50 uL of pyridine, and 50 uL of the diacid. The reaction isstirred for 12 h and NaOH (100 mg), 10 mL of MeOH, and 1 mL H₂O areadded. The reaction stirred 24 h and is concentrated and purified byHPLC (gradient elution, 20-40% MeCN in H₂O+5% isopropanol). LC/MS: m/z[M+H]⁺ 1322, R_(t)=1.2 (method 10).

Example 9 Preparation of Diacid 21 of Table A

Step 1:

To a solution of azide (100 mg, 0.087 mmol) in toluene (5 mL) is addedmethyl isonipecotinate hydrochloride (17.2 mg, 0.096 mmol) and molecularsieves at ambient temperature. The mixture is then heated to 70° C. andstirs for 12 h. The reaction is cooled to ambient temperature,concentrated and purified by flash chromatography (gradient elution:0-10% MeOH/DCM) which affords 90 mg of methyl ester. LC/MS: m/z [M+H]⁺1265.6, R_(t)=1.49 min (method 10).

Step 2:

To a solution of methyl ester (60 mg, 0.047 mmol) in DMF (2 mL) is addedmethyl bromovalerate (28 mg, 0.142 mmol) and cesium carbonate (46 mg,0.142 mmol) at ambient temperature. The mixture stirs at ambienttemperature for 4 days. Water is added to quench the reaction, theaqueous phase is extracted with 5% MeOH/DCM three times. Organic phasesare combined and dried over sodium sulfate, filtered, concentrated andpurified by flash chromatography (gradient elution: 0-10% MeOH/DCM)which affords 20 mg of dimethyl ester. LC/MS: m/z [M+2H]²⁺ 691,R_(t)=1.58 min (method 10).

Step 3:

To a solution of the dimethyl ester (20 mg, 0.015 mmol) in THF (2mL)/water (0.4 mL) is added LiOH (0.6 mL, 0.06 mmol, 0.1 M). Thereaction is stirred at ambient temperature for 4 h. 0.6 mL 0.1 M HCl isadded to quench the reaction, the mixture is concentrated and dilutedwith MeOH, the residue is purified by HPLC (10-60% acetonitrile inH₂O+0.1% ammonium hydroxide) furnishing 4.3 mg compound 21. LC/MS: m/z[M+2H]²⁺676, R_(t)=1.35 min (method 10).

Example 10 Preparation of Diacid 11 of Table A

Compound 11 is prepared according to the procedures described in example9. LC/MS: m/z [M+H]⁺ 1353, R_(t)=1.3 min (method 10). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.73 (d, J=13.14 Hz, 1H), 0.87 (dd, J=12.38, 6.82 Hz,6H), 1.28-1.57 (m, 8H), 1.88 (d, J=11.87 Hz, 1H), 2.12-2.23 (m, 1H),2.24-2.40 (m, 7H), 2.60 (s, 3H), 2.65-2.83 (m, 2H), 3.40 (s, 3H), 3.80(dd, J=16.80, 3.92 Hz, 1H), 4.17-4.37 (m, 3H), 4.96-5.07 (m, 3H),5.17-5.35 (m, 3H), 6.11 (br s, 1H), 7.19-7.35 (m, 5H), 7.37 (s, 1H),7.38-7.47 (m, 1H), 7.59 (s, 1H), 8.20 (d, J=8.08 Hz, 1H), 8.25 (s, 1H),8.40 (d, J=8.08 Hz, 1H), 8.42-8.49 (m, 1H), 8.60 (s, 1H), 8.69 (d,J=8.34 Hz, 2H), 9.01-9.10 (m, 1H), 9.84 (s, 1H).

Example 11 Preparation of Diacid 12 of Table A

Compound 12 is prepared according to the procedures described in example8. LC/MS: m/z [M+2H]⁺ 1325, R_(t)=1.3 min (method 10).

Example 12 Preparation of Diacid 13 of Table A

Compound 13 is prepared according to the procedures described in example2. LC/MS: m/z [M+H]⁺ 1375, R_(t)=0.64 min (method 10).

Example 13 Preparation of Diacid 14 of Table A

Compound 14 is prepared according to the procedures described in example8. LC/MS: m/z [M+2H]⁺ 1332, R_(t)=1.18 min (method 10).

Example 14 Preparation of Diacid 15 of Table A

Compound 15 is prepared according to the procedures described in example8. LC/MS: [M+2H]⁺ 1351, R_(t)=1.31 min (method 10).

Example 15 Preparation of Diacid 16 of Table A

Compound 16 is prepared according to the procedures described in example8. LC/MS: m/z [M+2H]⁺ 1351, R_(t)=1.22 min (method 10).

Example 16 Preparation of Diacid 17 of Table A

Compound 17 is prepared according to the procedures described in example8. LC/MS: m/z [M+2H]⁺ 1365, R_(t)=1.31 min (method 10).

Example 17 Preparation of Diacid 18 of Table A

Compound 18 is prepared according to the procedures described in example9. LC/MS: m/z [M+2F1]⁺ 1366, R_(t)=1.48 min (method 10).

Example 18 Preparation of Diacid 19 of Table A

Compound 19 is prepared according to the procedures described in example2. LC/MS: m/z [M+H]⁺ 1350, R_(t)=1. 3 min (method 5).

Example 19 Preparation of Diacid 20 of Table A

Compound 20 is prepared according to the procedures described in example2. LC/MS: m/z [M+H]⁺ 1382, R_(t)=1.2 min (method 5).

Example 20 Preparation of Diacid 22 of Table A

Compound 22 is prepared according to the procedures described in example9. LC/MS: m/z [M+2H]²⁺ 656, R_(t)=1. 34 min (method 10).

Example 21 Preparation of Diacid 23 of Table A

Compound 23 is prepared according to the procedures described in example9. LC/MS: m/z [M+2H]⁺ 1352, R_(t)=1. 47 min (method 10).

Example 22 Preparation of Diacid 24 of Table A

Compound 24 is prepared according to the procedures described in example2. LC/MS: m/z [M+2H]⁺ 1368, R_(t)=1. 28 min (method 5). ¹H NMR (DMSO-d6,400 MHz) δ ppm 0.78-0.98 (m, 6H), 1.21-1.36 (br, 1H), 1.39-1.55 (br,4H), 1.85-2.08 (br, 4H), 2.09-2.21 (m, 1H), 2.22-2.30 (br, 1H), 2.47 (s,3H), 2.60 (s, 3H), 2.68-2.76 (br, 1H), 3.39 (s, 3H), 3.71-3.85 (m, 3H),4.06 (s, 2H), 4.12-4.20 (br, 2H), 4.22-4.33 (m, 1H), 4.61-4.71 (br, 1H),4.94-5.03 (m, 3H), 5.17-5.34 (m, 3H), 5.96-6.10 (br, 1H), 7.18-7.43 (m,7H), 7.72 (s, 1H), 8.19-8.29 (m, 2H), 8.36-8.41 (m, 1H), 8.42-8.48 (m,1H), 8.60 (s, 1H), 8.69 (t, J=7.8, 7.8 Hz, 2H), 9.04 (d, J=7.70 Hz, 1H),12.04-12.81 (br, 2H).

Example 23 Preparation of Diacid 25 of Table A

Compound 25 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 6. LC/MS: m/z [M+H]⁺ 1480,R_(t)=1.39 min (method 6).

Step 1:

Chloro (1,1-dimethylethyl)dimethylsilane (1.10 g, 71 mmol) is added inportions over 5 min. to a solution of the alcohol (1.0 g, 6.30 mmol),imidazole (959 mg, 14.08 mmol) and DMF (4.2 mL) and the mixture isstirred under an atmosphere of N₂ for 3 h. The reaction mixture is thenpoured into 10% citric acid (18 mL) and extracted with ethyl acetate.The organic extracts are washed with water, brine, and then dried(Na₂SO₄) and purified by flash chromatography (eluent: ethylacetate/heptane, gradient) to afford the TBS ether (quant.). ¹H NMR (400MHz, CDCl₃) δ 3.61 (s, 3H), 2.20 (m, 1H), 1.85 (m, 4H), 1.50-1.20 (m,4H), 0.83 (s, 9H), 0.00 (s, 6H).

Step 2:

To a solution of LDA (367 uL, 0.734 mmol, 2 M in heptane/THF/ethylbenzene) in THF (1 mL) cooled to −70° C., the TBS ether (100 mg, 0.367mmol) is added in THF (1 mL). After 1 h at −70° C., allyl iodide (101uL, 1.10 mmol) is added and the solution is allowed to warm to roomtemperature and stirred for 2 h. It is then partitioned between ammoniumchloride and ethyl acetate. The organic layer is dried (Na₂SO₄) andpurified by flash chromatography (eluent: ethyl acetate/heptane,gradient) to afford the olefin (100 mg, 87%). ¹H NMR (400 MHz, CDCl₃) δ5.70 (m, 1H), 4.98 (m, 2H), 3.63 (s, 3H), 3.45 (m, 1H), 2.17 (m, 2H),1.58-1.10 (m, 7H), 0.84 (s, 9H), 0.00 (s, 6H).

Step 3:

To a solution of Grubbs II (11 mg, 0.013 mmol) in DCM (1.5 mL) are addedsimultaneously via syringe methyl-3-butenoate (139 uL, 1.29 mmol) andthe olefin (81 mg, 0.26 mmol). The reaction mixture is heated to 40° C.and is stirred for 12 h. The solvent is concentrated and purified byflash chromatography (eluent: ethyl acetate/heptane, gradient) to affordthe diester (75 mg, 75%). ¹H NMR (400 MHz, CDCl₃) δ 5.50-5.35 (m, 2H),3.64 (s, 6H), 3.50 (m, 1H), 3.00 (d, 2H), 2.15 (br, 4H), 1.80-1.10 (m,6H), 0.85 (s, 9H), 0.00 (s, 6H).

Step 4:

To a solution of the diester (200 mg, 0.52 mmol) in ethyl acetate (2.5mL) is added Pd/C (80 mg) under N₂ atmosphere. The reaction mixture ischarged with H₂ (balloon) and stirred for 2 h after which the reactionmixture is filtered through celite and concentrated to afford saturateddiester (172 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 3.63 (d, 6H), 3.50 (m,1H), 3.50 (m, 1H), 2.24 (t, 2H), 2.15 (d, 2H), 1.70-1.10 (m, 8H), 0.85(s, 9H), 0.00 (s, 6H).

Step 5:

To a solution of saturated diester (172 mg, 0.45 mmol) in THF (2 mL) isadded TBAF (890 mL, 0.89 mmol, 1 M solution in THF) and heated to 60° C.for 5 h. The reaction mixture is then concentrated and purified by flashchromatography (eluent: ethyl acetate/heptane, gradient) to afford thealcohol (90 mg). ¹H NMR (400 MHz, CDCl₃) δ 3.62 (s, 3H), 3.60 (s, 3H),3.50 (m, 1H), 2.18 (m, 4H), 1.8 (br, 2H), 1.80-1.10 (m, 10H).

Example 24 Preparation of Triacid 26 of Table A

Compound 26 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 7. LC/MS: m/z [M+H₂O]⁺ 1443,R_(t)=1.14 min (method 6).

Step 1:

To a solution of 2-nitrocyclohexanone (2.0 g, 18.97 mmol) in MeOH (28mL) is added methyl acrylate (1.4 mL, 15.37 mmol) and a catalytic amountof Ph₃P (10%). After stirring at room temperature for 12 h, an alcoholicsolution (209 mL) of KOH (20.9 mmol) is added and the solution is heatedat reflux for 8 h. After cooling to 0° C., an aqueous solution (209 mL)of KMnO₄ (16.70 mmol) and MgSO₄ (20.95 mmol) is slowly added, and afterthe complete addition, the reaction mixture is stirred for 18 h at roomtemperature, and then filtered through celite. After extraction withethyl acetate, the organic phase is dried, evaporated and the crudeproduct is purified by flash chromatography (eluent: ethylacetate/heptane, gradient) to afford 1.37 g of the ketone: ¹H NMR (400MHz, CDCl₃) δ 3.69 (s, 3H), 3.67 (s, 3H), 2.72 (m, 2H), 2.59 (m, 2H),2.48 (br, 2H), 2.33 (br, 2H), 1.63 (m, 4H).

Step 2:

To a solution of the ketone dimethylester (500 mg, 2.17 mmol) in MeOH(11 mL) is added NaBH₄ (41 mg, 1.08 mmol) at 0° C. The reactiontemperature is warmed to room temperature and stirred for 30 min. TLC(EtOAc/heptane, 6:4) showed complete conversion. The reaction mixture isconcentrated and purified by flash chromatography (eluent:EtOAc/heptane, gradient) to afford the alcohol (444 mg, 88%). ¹H NMR(400 MHz, CDCl₃) δ 4.42 (m, 1H), 3.60 (s, 6H), 1.81 (m, 4H), 1.75-1.43(m, 8H).

Example 25 Preparation of Diacid 27 of Table A

Compound 27 is prepared according to the procedures described in example2. LC/MS: m/z [M+2H]⁺ 1339, R_(t)=1.28 min (method 5).

Example 26 Preparation of Triacid 28 of Table A

Step 1:

To a solution of diisopropylamine (3.46 mL, 24.54 mmol) in THF (110 mL),is added n-BuLi (15.22 mL, 24.35 mmol) at 0° C. under nitrogen. Theresulting mixture is stirred for 15 mins at 0° C. To this solution at−78° C. is added dropwise a solution of dimethyl glutarate in THF (9mL), and the resulting mixture is stirred for 5 min. A solution of1,4-dibromobutene in THF (9 mL) and HMPA (9 mL) is then added at −78°C., and the stirring is continued for 2 h at −78° C. The reaction isquenched with 30 mL saturated aq NH₄Cl aqueous solution. The THF isremoved, and the material extracted with DCM (3×50 mL). The combinedorganic layers are concentrated, and the residue is purified by flashchromatography, eluting with hepatane/EtOAc to afford 600 mg of thebromide. LC/MS: m/z [M+H]⁺ 293, R_(t)=1.12 min (method 5).

Step 2:

To a solution of 101 (416 mg, 0.325 mmol) and Cs₂CO₃ (371 mg, 1.137mmol) in DMF (4.2 mL), is added the bromide (616 mg, 2.094 mmol). Thereaction is stirred at rt for 12 h, filtered (Cs₂CO₃), and concentrated.The residue is purified by flash chromatography, eluting with DCM/MeOH(gradient: 0-10%) to provide 290 mg (60%) of 102 as a yellow solid.LC/MS: m/z [M+H]⁺ 1492, R_(t)=1.73 min (method 5).

Step 3:

To a solution of 102 (290 mg, 0.194 mmol) in DCM (5 mL) and MeOH (16mL), is added 10% Pd/C (82 mg, 0.078 mmol), degassed and hydrogenated at50 psi for 12 h. The reaction is filtered, and additional 10% Pd/C (82mg, 0.078 mmol) and ammonium formate (240 mg, 3.82 mmol) are added. Thereaction stirred at reflux for two days and is filtered and purified byflash chromatography, then purified by HPLC (gradient elution, MeCN/H₂O,0.1% TFA) to afford 50 mg of 103. LC/MS: m/z [M+H]⁺ 1494, R_(t)=1.75 min(method 5).

Step 4:

To a solution of 103 (50 mg, 0.033 mmol) in THF (0.5 mL) and H₂O (0.3mL) is added 2 N LiOH (0.188 mL, 0.377 mmol) and the reaction mixture isstirred at rt for 25 h. The reaction is neutralized with NH₄Cl untilpH=6-7. The reaction mixture is concentrated under vacuum. The residueis dissolved in DMF/H₂O, purified with HPLC (0.1% TFA modified), andlyophilized for 12 h to provide 15 mg (30%) of 104, a light yellowsolid. LC/MS: m/z [M+2H]⁺ 1453, R_(t)=1.29 min (method 5).

Example 27 Preparation of Triacid 29 of Table A

Compound 29 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 10. LC/MS: m/z [M+H]⁺ 1466,R_(t)=1.18 min (method 6).

Step 1:

To a solution of oxalyl chloride (2.92 mL, 33.4 mmol) in DCM (139 mL) at−78° C. is added DMSO (4.74 mL, 66.8 mmol) and the mixture is stirredfor 30 minutes. A solution of alcohol (4.4 g, 27.8 mmol) in DCM (5 mL)is then added and the mixture is stirred for an additional 45 minutes.Finally, Et₃N (18.61 mL, 134 mmol) is added and the white solution isallowed to stir at −78° C. for 30 minutes before being warmed to 0° C.over 30 minutes. Saturated aqueous NH₄Cl is added to quench the reactionand the resulting mixture is extracted with DCM (3×100 mL). The combinedorganic extracts are dried (MgSO₄), filtered, and concentrated and theresidue is purified by flash chromatography (gradient elution: 0-50%EtOAc/heptane) furnishing 4.1 g of the ketone. ¹H NMR (400 MHz; CDCl₃) δ3.85 (s, 3H), 2.90 (m, 1H), 2.64-2.57 (m, 2H), 2.52-2.44 (m, 2H),2.37-2.32 (m, 2H), 2.20-2.10 (m, 2H).

Step 2:

To a solution of ketone (3.8 g, 24.3 mmol) in THF (57.9 mL) at −78° C.is added HMPA (23.2 mL), followed by KHMDS (51.1 mL, 25.5 mmol, 0.5 Msolution in toluene) and the resulting yellow solution is stirred for 30minutes. Allyl iodide (2.45 mL, 26.8 mmol) is added dropwise and thereaction mixture is allowed to stir at −78° C. for 30 minutes beforebeing warmed to room temperature over 10 minutes. Saturated aqueousNaHCO₃ is added to quench the reaction and the resulting mixture isextracted with EtOAc (3×100 mL). The combined organic extracts arewashed with brine, dried (MgSO₄), filtered and concentrated and theresidue is purified by flash chromatography (gradient elution: 0-50%EtOAc/heptane) furnishing 3.3 g of the olefin, ¹H NMR (400 MHz; CDCl₃) δ5.81-5.70 (m, 1H), 5.11-5.02 (m, 2H), 3.76 (s, 3H), 2.84 (t, 4.8 Hz,1H), 2.61-2.30 (m, 6H), 2.07-1.93 (m, 2H), 1.73-1.66 (ddd, 13.8, 10.4,4.7 Hz, 1H), followed by 985 mg of the isomer: ¹H NMR (400 MHz; CDCl₃) δ5.81-5.73 (m, 1H), 5.07-5.02 (m, 2H), 3.71 (s, 3H), 2.82 (t, 4.8 Hz, 1H), 2.61-2.30 (m, 6H), 2.09-1.81 (m, 2H), 1.61-1.50 (m, 1H).

Step 3:

To a solution of the olefin (310 mg, 1.58 mmol) and methyl-3-butenoate(843 μL, 7.90 mmol) in DCM (10 mL) at reflux is added a solution ofGrubb's II (67 mg, 5 mol %) and the resulting red mixture is stirred for3 hours. The solvent is evaporated and the residue is purified by flashchromatography (gradient elution: 0-50% EtOAc/heptane) furnishing 315 mgof the diester. ¹H NMR (400 MHz; CDCl₃) δ 5.66-5.47 (m, 2H), 3.75 (s,3H), 3.68 (s, 3H), 3.04 (d, 5.8 Hz, 2H), 2.86 (qd, 4.6 Hz, 1H),2.60-2.30 (m, 6H), 2.13-1.88 (m, 2H), 1.74-1.60 (m, 1H).

Step 4:

A solution of the diester (260 mg, 0.97 mmol) in EtOH (10 mL) is purgedwith N₂, and 10% Pd/C (26 mg, 10% w/w) is added. The mixture is againpurged with N₂, followed by H₂ and then maintained under an atmosphereof H₂ (balloon) for 1 hour. The reaction mixture is purged with N₂,filtered through a pad of celite and the filtrate concentrated tofurnish 261 mg of the saturated diester, which is used without furtherpurification.

Step 5:

To a solution of the saturated diester (261 mg, 0.97 mmol) in MeOH (10mL) at 0° C. is added NaBH₄ (18 mg, 0.49 mmol) and the resulting mixtureis allowed to stir for 30 minutes. Saturated aqueous NH₄Cl is added toquench the reaction and the resulting mixture is extracted with EtOAc(3×100 mL). The combined organic extracts are washed with brine, dried(MgSO₄), filtered and concentrated and the residue is purified by flashchromatography (gradient elution: 0-50% EtOAc/heptane) furnishing 200 mgof the alcohol. ¹H NMR (400 MHz; CDCl₃) δ 3.86-3.80 (m, 1H), 3.67 (s,3H), 3.66 (s, 3H), 2.58 (t, 4.8 Hz, 1H), 2.37-2.28 (m, 2H), 1.96-1.83(m, 1H), 1.76-1.22 (m, 13H).

Example 28 Preparation of Triacid 30 of Table A

Compound 30 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 11. LC/MS: m/z [M+H]²⁺ 714,R_(t)=1.18 min (method 6). ¹H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=7.8Hz, 1H), 8.69 (t, J=7.8 Hz, 2H), 8.61 (s, 1 H), 8.50-8.44 (m, 1H), 8.39(d, 8.0 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.73 (s, 1H),7.43-7.24 (m, 7H), 5.35-5.20 (m, 3H), 4.98 (br s, 3H), 4.33-3.75 (br m,8H), 3.39 (s, 3H), 2.79-2.66 (m, 1H), 2.59 (s, 3H), 2.28 (t, J=7.0 Hz,3H), 2.19 (t, J=7.0 Hz, 3H), 2.19-2.12 (m, 1H), 1.94-1.85 (m, 1H),1.83-1.73 (m, 1H), 1.73-1.62 (m, 3H), 1.62-1.40 (m, 8H), 1.34-1.11 (m,4H), 0.89 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H).

Step 1:

To a solution of γ-butyrolactone (10 g, 116 mmol) in THF (200 mL) at−78° C. is added LiHMDS (122 mL, 122 mmol, 1.0 M solution in THF). Afterstirring for 30 minutes 1,3-dimethyl-2-imidazolidinone (15.1 mL, 139mmol), followed by allyl bromide (11.1 mL, 128 mmol) are added and theresulting mixture is allowed to stir for 1 hour. Saturated aqueous NH₄Clis added to quench the reaction and the resulting mixture is extractedwith EtOAc (3×100 mL). The combined organic extracts are washed withbrine, dried (MgSO₄), filtered and concentrated and the residue ispurified by flash chromatography (gradient elution: 0-50% EtOAc/heptane)furnishing 14.6 g of the olefin.

Step 2:

To a solution of the olefin (14.6 g, 116 mmol) in MeOH (100 mL) at roomtemperature is added KOH (13.0 g, 232 mmol) and the resulting mixture isstirred for 3 hours. The solvent is removed from the reaction and theresidue is partitioned between H₂O and Et₂O. The layers are separatedand the aqueous phase is extracted with Et₂O (2×50 mL). The aqueousphase is then acidified to pH 3 with HCl (1 M) and extracted with EtOAc(3×100 mL). The combined organic extracts are washed with brine, dried(MgSO₄), filtered and concentrated furnishing 16.6 g of the acid whichis used without further purification.

Step 3:

To a solution of the acid (16.6 g, 116 mmol) in MeOH (200 mL) and Et₂O(500 mL) at 0° C. is added (trimethylsilyl)diazomethane (76 mL, 151mmol, 2.0 M solution in Et₂O, enough to maintain a yellow color in thereaction mixture). The solvent is removed from the reaction mixture andthe residue is purified by flash chromatography (gradient elution: 0-60%EtOAc/heptane) furnishing 18.3 g of the ester.

Step 4:

To a solution of the ester (18.3 g, 116 mmol) in DMF (150 mL) at roomtemperature is added imidazole (9.49 g, 139 mmol), followed by TBSCl(19.3 g, 128 mmol) and the resulting mixture is stirred for 8 hours. Thereaction mixture is diluted with H₂O, extracted with Et₂O (3×100 mL) andthe combined extracts are washed with H₂O (2×100 mL), saturated aqueousNaHCO₃ and brine, then dried (MgSO₄), filtered and concentrated. Theresidue is purified by flash chromatography (gradient elution: 0-30%EtOAc/heptane) furnishing 30.6 g of the TBS ether. ¹H NMR (400 MHz;CDCl₃) δ 5.82-5.63 (m, 1H), 5.14-4.94 (m, 2H), 3.67 (s, 3H), 3.67-3.58(m, 2H), 2.73-2.57 (m, 1H), 2.38-2.18 (m, 2H), 1.96-1.79 (m, 1H),1.79-1.58 (m, 1H), 0.89 (s, 9H), −0.04 (s, 6H).

Step 5:

The olefin is prepared in an identical manner to that describedpreviously for example 27 and purified by flash chromatography (gradientelution: 0-30% EtOAc/heptane) furnishing 420 mg. ¹H NMR (400 MHz; CDCl₃)δ 5.65-5.43 (m, 2H), 3.68 (s, 3H), 3.66 (s, 3H), 3.66-3.54 (m, 2H), 3.04(d, 6.6 Hz, 2H), 2.68-2.57 (m, 1H), 2.41-2.21 (m, 2H), 1.94-1.81 (m,1H), 1.74-1.51 (m, 1H), 0.89 (s, 9H), −0.03 (s, 6H).

Step 6:

The saturated diester is prepared in an identical manner to thatdescribed previously for example 27 and purified by flash chromatography(gradient elution: 0-30% EtOAc/heptane) furnishing 340 mg. ¹H NMR (400MHz; CDCl₃) δ 3.67 (s, 6H), 3.65-3.54 (m, 2H), 2.59-2.48 (m, 1H), 2.30(t, 7.5 Hz, 2H), 1.92-1.80 (m, 1H), 1.71-1.43 (m, 3H), 1.39-1.19 (m,4H), 0.89 (s, 9H), −0.04 (s, 6H).

Step 7:

To a solution of the saturated diester (289 mg, 0.83 mmol) in DCM (8 mL)and MeOH (8 mL) at −10° C. is added CSA (213 mg, 0.92 mmol) and theresulting mixture is stirred for 1 hour. Saturated aqueous NaHCO₃ isadded to quench the reaction and the resulting mixture is extracted withDCM (3×20 mL). The combined organic extracts are washed with saturatedaqueous NaHCO₃, brine, dried (MgSO₄), filtered and concentrated and theresidue is purified by flash chromatography (gradient elution: 0-80%EtOAc/heptane) furnishing 190 mg of the alcohol. ¹H NMR (400 MHz; CDCl₃)δ 3.69 (s, 3H), 3.69-3.63 (m, 2H), 3.66 (s, 3H), 2.61-2.48 (m, 1H), 2.30(t, 7.5 Hz, 2H), 1.95-1.80 (m, 1H), 1.80-1.56 (m, 4H), 1.56-1.39 (m,1H), 1.39-1.17 (m, 2H).

Example 29 Preparation of Triacid 31 of Table A

Compound 31 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 12. LC/MS: m/z [M+2H]⁺ 1495,R_(t)=1.44 (method 5).

Step 1:

To a solution of valerolactone (contaning 25% polymer, 5 g, 37.5 mmol)in THF (100 mL) at −78° C., is added LHMDS (52.4 mL) over 20 min. Thesolution is stirred for 0.5 h, then 1,3-dimethyl-2-imidazolidinone (6.84g, 59.9 mmol) and allyl idodide (5.02 mL, 54.9 mmol) is added, and thereaction is stirred for 1 h. The reaction is quenched with saturatedNH₄Cl aqueous solution (50 mL). The mixture is extracted by EtOAc (250mL), washed with saturated NaHCO₃ and brine. The EtOAc layer isconcentrated and the residue is purified by flash chromatography,eluting with heptane/EtOAc to afford 3.4 g (64.8% yield) of the olefin.

Step 2:

To a solution of the olefin (1.1 g, 7.854 mmol) and 5-hexenoic acidmethylester (5.03 g, 39.226 mmol) in DCM (110 mL) at reflux is added asolution of Grubbs II (332 mg, 0.392 mmol) in DCM (11 mL) and theresulting mixture is stirred for 1 hour at reflux. The residue ispurified with flash chromatography, eluting with hepatane/EtOAc toafford 1.227 g (65% yield) of the lactone.

Step 3:

The lactone (1.227 g, 5.11 mmol) and 10% Pd/C(0.893 g, 0.842 mmol) aremixed in MeOH (60 mL). The reaction is degassed and hydrogenated for 2h. TLC showed disappearance of starting material. The reaction isfiltered and concentrated to afford 1.2 g of crude diester-alcohol.

Step 4:

The diester-alcohol (300 mg, 1.093 mmol) and Ph₃P (315 mg, 1.203 mmol)are dissolved in CH₂Cl₂ (13 mL), and cooled in an ice bath. CBr₄ (363mg, 1.083 mmol) is added with stirring. The mixture is allowed to warmto rt and is stirred for 12 h. The reaction mixture is concentrated andpurified with flash chromatography, eluting by heptane/EtOAc to afford220 mg (60% yield) of the bromide. ¹H NMR (CDCl₃, 400 MHz) δ 1.30(broad, 6H) 1.45 (broad, 1H) 1.63 (broad, 5H) 1.85 (m, 2H) 2.30 (t, 2H)2.35 (m, 1H) 3.40 (t, 2H) 3.67 (s, 6H).

Example 30 Preparation of Triacid 32 of Table A

Compound 32 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 13. LC/MS: m/z [M+H]⁺ 1426,R_(t)=1.05 min (method 6).

Step 1:

To a solution of the ester (1.0 g, 3.7 mmol) in THF (20 mL) at −10° C.is added DIBAL-H (8.44 mL, 8.4 mmol, 1.0 M solution in hexanes) dropwiseand the resulting mixture is stirred for 1 hour. MeOH (10 mL),Rochelle's Salt (100 mL) and EtOAc (100 mL) are added and the biphase isstirred vigorously for 3 h. The layers are separated and the aqueousphase is extracted with EtOAc (3×100 mL). The combined extracts arewashed with brine, dried (MgSO₄), filtered and concentrated furnishing895 mg of the alcohol, which is used without further purification. ¹HNMR (400 MHz; CDCl₃) δ 5.86-5.71 (m, 1H), 5.09-4.98 (m, 2H), 3.78 (ddd,10.4, 6.2, 4.0 Hz, 1H), 3.71-3.57 (m, 2H), 3.52-3.43 (m, 1H), 3.11-2.82(br s, 1H), 2.18-1.97 (m, 2H), 1.82-1.63 (m, 2H), 1.59-1.47 (m, 1H),0.91 (s, 9H), 0.08 (s, 6H).

Step 2:

To a solution of the alcohol (895 mg, 3.7 mmol) in DMF (12 mL) at roomtemperature is added NaH (220 mg, 5.5 mmol). After stirring for 30minutes, benzyl bromide (524 μL, 4.4 mmol) and tetrabutylammonium iodide(678 mg, 1.8 mmol) are added and the resulting mixture is allowed tostir 12 h. Saturated aqueous NH₄Cl is added to quench the reaction andthe resulting mixture is diluted with EtOAc (100 mL). The layers areseparated and the organic phase is washed with H₂O (3×30 mL), brine,then dried (MgSO₄), filtered and concentrated and the residue ispurified by flash chromatography (gradient elution: 0-30% EtOAc/heptane)furnishing 1.22 g of the benzyl ether. ¹H NMR (400 MHz; CDCl₃) δ7.43-7.24 (m, 5H), 5.86-5.70 (m, 1H), 5.11-4.96 (m, 2H), 4.50 (s, 2H),3.73-3.61 (m, 1H), 3.61-3.45 (m, 1H), 3.45-3.34 (m, 1H), 2.28-2.00 (m,2H), 1.95-1.83 (m, 1H), 1.77-1.49 (m, 3H), 0.90 (s, 9H), 0.05 (s, 6H).

Step 3:

To a solution of the benzyl ether (1.32 g, 4.0 mmol) in THF (20 mL) at0° C. is added TBAF (5.92 mL, 5.9 mmol, 1.0 M solution in THF) and theresulting mixture is allowed to warm to room temperature and stirred for2 hours. Saturated aqueous NH₄Cl is added to quench the reaction and theresulting mixture is diluted with EtOAc (50 mL). The layers areseparated and the aqueous phase is extracted with EtOAc (3×30 mL). Thecombined organic extracts are washed with brine, then dried (MgSO₄),filtered and concentrated and the residue is purified by flashchromatography (gradient elution: 0-80% EtOAc/heptane) furnishing 865 mgof the alcohol. ¹H NMR (400 MHz; CDCl₃) δ 7.41-7.24 (m, 5H), 5.84-5.68(m, 1H), 5.09-4.94 (m, 2H), 4.53 (s, 2H), 3.76-3.58 (m, 2H), 3.49 (dd,9.2, 7.2 Hz, 1 H), 3.37 (dd, 9.2, 7.2 Hz, 1H), 2.56 (br s, 1H),2.21-2.01 (m, 2H), 1.98-1.84 (m, 1H), 1.79-1.65 (m, 1H), 1.65-1.52 (m,1H).

Step 4:

To a solution of the alcohol (600 mg, 2.7 mmol) in DCM (14 mL) at roomtemperature is added Dess-Martin periodinane (1.4 g, 3.3 mmol) and theresulting mixture is stirred for 1 hour. The reaction mixture is dilutedwith Et₂O (50 mL) and a solution of Na₂S₂O₃ (5.5 g) in saturated aqueousNa₂CO₃ (10 mL) is added and the biphase is stirred until clear. Thelayers are separated and the organic phase is washed with saturatedaqueous Na₂CO₃, brine, then dried (MgSO₄), filtered and concentrated andthe residue is purified by flash chromatography (gradient elution: 0-30%EtOAc/heptane) furnishing 535 mg of the aldehyde. ¹H NMR (400 MHz;CDCl₃) δ 9.77 (s, 1H), 7.38-7.27 (m, 5H), 5.80-5.69 (m, 1 H), 5.10-5.03(m, 2H), 4.48 (s, 2H), 3.49 (dd, 9.2, 4.7 Hz, 1H), 3.33 (dd, 9.2, 6.7Hz, 1H), 2.51-2.37 (m, 2H), 2.32-2.16 (m, 1H), 2.12-2.02 (m, 1H),1.33-1.22 (m, 1H).

Step 5:

To a solution of the aldehyde (535 mg, 2.5 mmol) and 2-methyl-2-butene(2.6 mL, 24.5 mmol) in H₂O (6 mL) and tert-butanol (6 mL) at roomtemperature is added a solution of NaH₂PO₄ (1.47 g, 12.3 mmol) in H₂O(500 μL) followed by a solution of NaClO₂ (665 mg, 7.4 mmol) in H₂O (500μL). The resulting mixture is allowed to stir for 15 minutes, then brine(10 mL) is added and the mixture is extracted with CHCl₃ (3×15 mL). Thecombined organic extracts are dried (Na₂SO₄), filtered and concentratedfurnishing 574 mg of the acid which is used without furtherpurification.

Step 6:

The ester is prepared in an identical manner to that describedpreviously for example 28 and purified by flash chromatography (gradientelution: 0-30% EtOAc/heptane) furnishing 470 mg. ¹H NMR (400 MHz; CDCl₃)δ 7.37-7.26 (m, 5H), 5.81-5.70 (m, 1H), 5.09-5.01 (m, 2H), 4.49 (s, 2H),3.69 (s, 3H), 3.46 (dd, 9.3 5.1 Hz, 1H), 3.38 (dd, 9.3, 6.3 Hz, 1H),2.45-2.18 (m, 3H), 2.13-2.08 (m, 1H), 1.35-1.24 (m, 1H).

Step 7:

The olefin metathesis product is prepared in an identical manner to thatdescribed previously for example 27 and purified by flash chromatography(gradient elution: 0-30% EtOAc/heptane) furnishing 500 mg. ¹H NMR (400MHz; CDCl₃) δ 7.37-7.26 (m, 5H), 5.62-5.43 (m, 2H), 4.52-4.43 (m, 2H),3.68 (s, 3H), 3.63 (s, 3H), 3.43 (dd, 9.2, 4.8 Hz, 1 H), 3.36 (dd, 9.2,5.9 Hz, 1H), 2.43-2.06 (m, 7H).

Step 8:

The alcohol is prepared in an identical manner to that describedpreviously in example 27 and purified by flash chromatography (gradientelution: 0-80% EtOAc/heptane) furnishing 200 mg. ¹H NMR (400 MHz; C₆D₆)δ 3.37 (dd, 10.6, 4.5 Hz, 1H), 3.35 (s, 3H), 3.33 (s, 3H), 3.25 (dd,10.6, 6.3 Hz, 1H), 2.29 (dd, 15.7, 7.6 Hz, 1H), 2.12 (dd, 15.7, 5.8 Hz,1H), 2.05 (t, 7.5 Hz, 2H), 1.92-1.85 (m, 1H), 1.49-1.36 (m, 3H),1.19-1.02 (m, 3H).

Example 31 Preparation of Triacid 33 of Table A

Compound 33 is prepared according to the procedures described in example23, using the following deprotection conditions (MgI₂).

To the suspension of the triester (24 mg, 0.016 mmol) in toluene isadded magnesium iodide (27 mg, 0.095 mmol) and the reaction mixture isheated to 100° C. for 12 h. The reaction mixture is concentrated andre-dissolved in DMF and filtered, purified by HPLC (40 to 80% CAN inwater, 0.1% TFA). The fractions are collected and lyophilized to afford33 (1.3 mg). LC/MS: m/z [M+2H]⁺ 1467, R_(t)=1.05 min (method 6). ¹H NMR(400 MHz, DMSO-d6) δ ppm 9.10 (d, 2H), 8.54 (t, 2H), 8.52 (s, 3H), 8.49(m, 1H), 8.47 (d, 1H), 8.25 (s, 1H), 8.2 (d. 1H), 7.75 (s, 1H), 7.4-7.2(m, 7H), 6.05 (s, 1H), 5.35-5.15 (m, 3H), 4.9 (m, 3H), 4.65 (s, 1H),4.25 (m, 1H), 3.9 (s, 1H), 3.8 (d, 1H), 3.35 (s, 3H), 2.65 (m, 1H), 2.6(s, 3H), 2.35-1.75 (m, 10H), 1.70-1.10 (m, 16H), 0.85 (m, 6H).

Example 32 Preparation of Triacid 34 of Table A

Compound 34 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 14. LC/MS: m/z [M+H]⁺ 1467,R_(t)=1.45 min (method 6).

Step 1:

To a solution of oxalyl chloride in DCM (120 mL) at −70° C. is addedDMSO (5.60 mL, 79 mmol). Then to the mixture, a solution of the alcohol(5.0 g, 31.6 mmol) in DCM (940 mL) is added dropwise within 2 min. Themixture is stirred for 15 min. at −70° C. After addition of i-Pr₂EtN,the mixture is allowed to reach room temperature and poured in to water(300 mL). The aqueous phase is extracted with DCM (30 mL). The combinedextracts are dried over Na₂SO₄, filtered, concentrated and then purifiedby flash chromatography (eluent: EtOAc/heptane, gradient) to afford theketone (2.8 g). ¹H NMR (400 MHz, CDCl₃) δ 3.80 (s, 3H), 2.84 (m, 1H),2.53 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 2.15 (m, 2H).

Step 2:

A solution of the ketone (500 mg, 3.20 mmol) in THF (20 mL) is cooled to−50° C. and allyl magnesium bromide (3.2 mL, 3.20 mmol) is added and thereaction stirred for 30 min. To the reaction mixture is added sat. aqNH₄Cl and the product is extracted with ethyl acetate, dried overNa₂SO₄, and purified by flash chromatography (eluent: EtOAc/heptane,gradient) to afford the alcohol (150 mg). ¹H NMR (400 MHz, CDCl₃) δ 5.89(m, 1H), 5.19 (m, 2H), 3.70 (s, 3H), 2.47 (m, 1H), 2.29 (d, 2H), 1.74(m, 3H), 1.51-1.40 (m, 3H).

Step 3:

The diester is synthesized according to the procedure described inexample 27. Obtained 122 mg, ¹H NMR (400 MHz, CDCl₃) δ 5.67 (m, 2H),3.71 (s, 3H), 3.17 (d, 2H), 2.30 (m, 1H), 2.29 (d, 2H), 1.91 (m, 2H),1.69 (m, 3H), 1.47 (m, 2H).

Step 4:

The saturated diester-alcohol is synthesized according to the proceduredescribed in example 27. Obtained 120 mg: ¹H NMR (400 MHz, CDCl₃) δ 3.61(s, 6H), 2.35 (m, 1H), 2.25 (m, 4H), 1.8 (m, 2H), 1.80-1.10 (m, 10H).

Example 33 Preparation of Diacid 35 of Table A

Compound 35 is prepared according to the procedures described in example2, using the alcohol prepared in scheme 11. LC/MS: m/z [M+H]⁺ 1326,R_(t)=1.04 min (method 6).

Example 34 Preparation of Diacid 2 of Table A

Step 1:

To a solution of the diester-acid (1 g, 4.6 mmol) in DCM (20 mL) isadded oxalyl chloride (1.9 mL, 22.2 mmol), followed by 20 μL of DMF. Thereaction is stirred for 90 min at 22° C. Reaction proceeds to a clearsolution after 60 min. Volatiles are removed by concentration with DCMto afford 1.08 g (4.6 mmol, quant.) of a pale yellow solid that is usedwithout further handling.

Step 2:

Hydrochloric acid is bubbled through a solution of acetate protectedboc-amine (as prepared in example 8, scheme 4; 1.4 g, 1.1 mmol) in DCM(20 mL) for thirty min. The reaction mixture is then tightly capped andstirred for thirty minutes after which the reaction mixture is spargedwith nitrogen. The mixture loses its gel like appearance. DCM (5 mL) isadded to the solution, and HCl gas is bubbled through it for anadditional 20 min, followed by nitrogen for 30 min. Crude product (1.32g) is obtained after concentration as a bright orange solid, and takenon to the next step with no further purification. LC/MS: m/z [M+H]⁺1138, R_(t)=1.5 min (method 1).

Step 3:

To a solution of the amine (1.24 g, 1.1 mmol) in DCM (120 mL), is addedpyridine (445 μL, 5.5 mmol), followed by the acid chloride (0.510 g, 2.2mmol). The reaction is stirred at 22° C. for 20 minutes. Subsequently,SiO₂ is added, and the resulting mix is concentrated to afford a slurry.Purification using flash column chromatography (elution with 500 mL of50% EtOAc/heptane, 500 mL 75% EtOAc/heptane, to 1 L 100% EtOAc) affords1.29 g (0.97 mmol, 88% yield) of a pale yellow solid that is usedwithout further modification.

Step 4:

To a solution of the diester (0.42 g, 0.31 mmol) in MeOH (30 mL) and H₂O(10 mL) is added NaOH crystals (53 mg, 1.3 mmol) and this mixture isstirred at 22° C. for 24 hrs. The mixture is then concentrated todryness. HPLC purification (30-100% ACN/H₂O in 0.1% TFA, 10 min) thenlypholization affords 300 mg (0.24 mmol, 77%) as a pale yellow solid,LC: R_(t)=10.24 min. ¹H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.15 (s, 2H),9.12 (s, 1 H), 8.69 (d, 1H), 8.68 (d, 1H), 8.65 (d, 1H), 8.59 (s, 1H),8.43 (d, 1H), 8.37 (d, 1H), 8.25 (s, 1H), 8.16 (d, 1H), 7.82 (s, 1H),7.46 (s, 1H), 7.37 (s, 1H), 7.32 (d, 1H), 7.29 (t, 1H), 7.24 (t, 1H),6.36 (s, 1H), 5.30 (m, 1H), 5.24 (t, 1H), 5.21 (dd, 1H), 5.01 (d, 1H),4.98 (s, 2H), 4.28 (dd, 1H), 3.80 (dd, 1H), 3.39 (s, 3H), 2.78 (m, 1H),2.71 (m, 2H), 2.70 (m, 1H), 2.59 (s, 3H), 2.49 (d, 3H), 2.45 (m, 1H),2.32 (m, 2H), 2.17 (m, 1H), 1.95 (m, 1H), 1.64 (m, 1H), 1.37 (m, 1H),0.88 (d, 3H), 0.86 (d, 3H). HRMS (ES+) for C₅₄H₅₃N₁₃O₁₂S₆: Calc:[M+2H]²⁺ 634.6198; Found: 634.6197.

Example 35 Preparation of Diacid 1 of Table A

Compound 1 is prepared according to the procedures described in example34. LC: R_(t)=10.05 min. ¹H NMR (DMSO-d6, 400 MHz) δ (ppm) 13.5 (s, 2H),9.24 (s, 1H), 8.73 (d, 1 H), 8.68 (d, 1H), 8.65 (d, 1H), 8.59 (s, 1H),8.43 (d, 1H), 8.37 (d, 1H), 8.23 (s, 1H), 8.16 (d, 1H), 7.77 (s, 1H),7.46 (s, 1H), 7.37 (s, 1H), 7.32 (d, 1H), 7.29 (t, 1H), 7.24 (t, 1H),6.36 (s, 1H), 5.30 (m, 1H), 5.25 (t, 1H), 5.21 (dd, 1H), 5.01 (d, 1H),4.98 (s, 2H), 4.28 (dd, 1H), 3.81 (dd, 1H), 3.39 (s, 3H), 2.78 (m, 1H),2.71 (m, 2H), 2.70 (m, 1H), 2.59 (s, 3H), 2.49 (d, 3H), 2.45 (m, 1H),2.32 (m, 2H), 2.17 (m, 1H), 2.09 (m, 1H), 1.75 (m, 1H), 1.31 (m, 1H),0.88 (d, 3H), 0.86 (d, 3H). HRMS (ES+) for C₅₄H₅₃N₁₃O₁₂S₆: Calc:[M+2H]²⁺=634.6198; Found: 634.6197.

Biological Results:

Using the standard MIC test described above with the bacteriaEnterococcus faecalis, Enterococcus faecium or Staphylococcus aureus,compounds 1-35 demonstrate a minimum inhibitory concentration rangingfrom 0.0010 μg/mL to 128 μg/mL.

In vitro assay for inhibition of prokaryotic transcription-translation[as described in the following references: 1. Zubay, G. (1973) In vitrosynthesis of protein in microbial systems. Annu. Rev. Genet. 7, 267.87.2. Zubay, G. (1980) The isolation and properties of CAP, the catabolitegene activator. Meth. Enzymol. 65, 856.77]. Antibiotic and compounddilutions: stock solutions of compound to be assayed at 2 μM are 80 μMin 40% DMSO. Stock solutions of compounds to be assayed at 10 μM are 400μM in 40% DMSO.

Assay setup and protocol for Promega E. coli S30 Extract System

TABLE 1 E. coli S30 Extract system master mix Component Final volume (16μl) “Methionine minus” amino acid mix 1.0 μl “Cysteine minus” amino acidmix 1.0 μl S30 premix 8.0 μl S30 extract 6.0 μl

TABLE 2 E. coli S30 Extract system assay components Final volumeComponents/Reagents (20 μl total volume) Template (pBESTluc ™) 286 ng/μl3.5 μl Compound (40x final concentration) 0.5 μl in 40% DMSO Master mix(see table 1) 16 μl

The assay is performed as follows: pipet 3.5 p. 1 of 286 ng/μl templateDNA (pBESTluc™) into assay wells. Negative control wells receive sdH₂Oonly. Transfer 0.5 μl of 40× compound stock solution to assay wells.Positive control wells (no compound) receive 0.5 μl 40% DMSO sdH₂O.Pipet 16 μl of master mix into assay wells. Incubate plate for two hoursat 37° C. Rapidly chill the assay plate on ice for five minutes to stopthe reaction. Add an equal volume (20 p. 1) of room temperatureSteady-Glo® Luciferase assay reagent to all assay wells. Incubate 20minutes and read light emitted with luminometer. Results are reported as% inhibition @ 2 μM or 10 μM.

TABLE 2  (1) % inh. @  (2) % inh. @  (3) % inh. @ 2 uM = 65.4 2 uM =72.8 2 uM = 67.8  (4) % inh. @  (5) % inh. @  (6) % inh. @ 2 uM = 85.3 2uM = 78.5 2 uM = 86.8  (7) % inh. @  (8) % inh. @  (9) % inh. @ 2 uM =86.0 2 uM = 59.7 2 uM = 67.1 (10) % inh. @ (11) % inh. @ (12) % inh. @ 2uM = 2.0 2 uM = 92.3 2 uM = 82.4 (13) % inh. @ (14) % inh. @ (15) % inh.@ 2 uM = 74.9 2 uM = 55.5 2 uM = 64.5 (16) % inh. @ (17) % inh. @ (18) %inh. @ 2 uM = 64.3 2 uM = 63.9 2 uM = 52.7 (19) % inh. @ (20) % inh. @(21) % inh. @ 2 uM = 76.4 2 uM = 80.6 2 uM = 37.4 (22) % inh. @ (23) %inh. @ (24) % inh. @ 2 uM = 79.8 2 uM = 79.8 2 uM = 70.3 (25) % inh. @(26) % inh. @ (27) % inh. @ 2 uM = 83.7 2 uM = 68.2 2 uM = 81.9 (28) %inh. @ (29) % inh. @ (30) % inh. @ 2 uM = 77.0 2 uM = 79.6 2 uM = 83.93(31) % inh. @ (32) % inh. @ (33) % inh. @ 2 uM = 79.4 2 uM = 78.0 2 uM =46.8 (34) % inh. @ (35) % inh. @ 2 uM = 63.1 2 uM = 87.0

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims.

What is claimed is:
 1. A compound of the formula I:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof; wherein R¹ is —Z—CO₂H and-A-Z—CO₂H; R^(1a) is hydrogen, —Z—CO₂H, and -A-Z—CO₂H, wherein if R^(1a)is hydrogen, then the Z residue of R¹ is substituted by at least twoCO₂H groups; or R¹ and R^(1a), taken in combination, form a saturated,partially unsaturated or aromatic heterocycle having 4 to 7 ring atomsand having 0-3 additional ring heteroatoms selected from N, O and S,wherein the heterocycle is substituted by at least two residuesindependently selected from CO₂H, —Z—CO₂H, and -A-Z—CO₂H; A isindepenendently selected at each occurrence from the group consisting ofa —C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—, —C(H)═N—,—S(O)₂N(R^(8a))—, and —S(O)N(R^(8a))—; Z is C₁-C₁₀alkylene,C₃-C₈cycloalkylene, C₃-C₈heterocycloalkylene, phenylene, or 5-6 memberedheteroarylene, each of which is optionally substituted with one or moregroups independently selected from C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy,amino, mono- and di-C₁-C₆alkylamino, C(O)OH, or halogen; R^(2a) isselected from the group consisting of H, substituted or unsubstitutedalkyl, OH, OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; R^(2b)is selected from the group consisting of absent, H and alkyl, or R^(2a)and R^(2b) may together form ═O or ═NH; R³ an R¹² are each,independently, selected from the group consisting of H, halogen,OR^(4b), -A-J, and N(R^(8a))₂; R^(4a) is selected from the groupconsisting of H, and alkyl; R^(4b) is selected from the group consistingof alkyl and —(CH₂—CH₂—O—)_(n)—R⁹, wherein n is an integer of 1-500,1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000,50,000, or 60,000 or is a mean of a plurality of integers having a valueof 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000,40,000, 50,000, or 60,000; R⁵ is selected from the group consisting ofH, alkyl, and R^(4b); J is selected from the group consisting of H, F,O-alkyl, N(R^(8a))₂, N⁺(R^(8a))₃, N(R^(8a))C(O)alkyl, CO₂H,C(═O)N(R^(8a))₂, CO₂-alkyl, P(O)(OH)₂, P(O)(O-alkyl)₂, and a substitutednitrogen-containing heterocycle; R^(8a) is absent, or selected from thegroup consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl)₂-J, —R^(4b),wherein R^(8a) can also cyclize with the atom to which R^(8a) is bondedto form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromaticand may contain one or more heteroatoms, wherein the ring may be furthersubstituted one or more times with substitutents that are the same ordifferent; and R⁹ is selected from the group consisting of H, alkyl andCH₂CO₂H.
 2. The compound of claim 1, wherein R^(2b), R^(4b) and R⁵ areH, and R^(4a) is CH₃.
 3. The compound of claim 1, wherein R^(2b), R^(4b)and R⁵ are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃.
 4. The compound ofclaim 1, wherein formula I is represented by a compound of formula II:

and pharmaceutically acceptable salts thereof.
 5. The compound of claim1, wherein formula I is represented by a compound of formula III:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof.
 6. The compound of claim 5,wherein R^(2b), R^(4b) and R⁵ are H, and R^(4a) is CH₃.
 7. The compoundof claim 5, wherein R^(2b), R^(4b) and R⁵ are H, R^(4a) is CH₃, and R¹²is CH₂—O—CH₃.
 8. The compound of claim 5, wherein formula III isrepresented by a compound of formula IV:


9. The compound of claim 8, wherein A is selected from the groupconsisting of —C(O)O—, C(O)—NH—, —C(O)—, —S(O)₂—, and —S(O)₂NH—; and Zis independently selected at each occurrence from the group consistingof C₁-C₁₀alkylene,


10. The compound of claim 1, wherein formula I is represented by acompound of formula V:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof, wherein D represents a five orsix membered heterocyclic ring which is saturated or aromatic, whichring comprises 0-2 additional ring heteroatoms selected from N, O or S.11. The compound of claim 10, wherein R^(2b), R^(4b) and R⁵ are H, andR^(4a) is CH₃.
 12. The compound of claim 10, wherein R^(2b), R^(4b) andR⁵ are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃.
 13. The compound of claim10, wherein formula V is represented by a compound of formula VI:


14. The compound of claim 13, wherein A is selected from the groupconsisting of —C(O)O—, C(O)—NH—, —C(O)—, —S(O)₂—, and —S(O)₂NH—; and Zis independently selected at each occurrence from the group consistingof C₁-C₁₀alkylene,


15. The compound of claim 1, wherein R^(2a) is OH or OAc.
 16. Thecompound of claim 1, wherein the core pyridine functionality is of thefollowing N-oxide formula:


17. A compound selected from the group consisting of:


18. A compound of formula VII:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof; wherein R¹ is —Z—CO₂H and-A-Z—CO₂H; R^(1a) is hydrogen, —Z—CO₂H, and -A-Z—CO₂H, wherein if R^(1a)is hydrogen, then the Z residue of R¹ is substituted by at least twoCO₂H groups; or R¹ and R^(1a), taken in combination, form a saturated,partially unsaturated or aromatic heterocycle having 4 to 7 ring atomsand having 0-3 additional ring heteroatoms selected from N, O and S,wherein the heterocycle is substituted by at least two residuesindependently selected from CO₂H, —Z—CO₂H, and -A-Z—CO₂H; A isindepenendently selected at each occurrence from the group consisting ofa —C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—, —C(H)═N—,—S(O)₂N(R^(8a))—, and —S(O)N(R^(8a))—; Z is C₁-C₁₀alkylene,C₃-C₈cycloalkylene, C₃-C₈heterocycloalkylene, phenylene, or 5-6 memberedheteroarylene, each of which is optionally substituted with one or moregroups independently selected from C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy,amino, mono- and di-C₁-C₆alkylamino, C(O)OH, or halogen; R² is hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₀₋₆alkyl,C₃₋₇cycloalkylC₀₋₄alkyl, arylC₀₋₄alkyl, or a residue of the formula:

R^(2a) is selected from the group consisting of H, substituted orunsubstituted alkyl, OH, OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ andN(R^(8a))₂; R^(2b) is selected from the group consisting of absent, Hand alkyl, or R^(2a) and R^(2b) may together form ═O or ═NH; R³ an R¹²are each, independently, selected from the group consisting of H,halogen, OR^(4b), -A-J, and N(R^(8a))₂; R^(4a) is selected from thegroup consisting of H, and alkyl; R^(4b) is selected from the groupconsisting of alkyl and —(CH₂—CH₂—O—)_(n)—R⁹, wherein n is an integer of1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000,40,000, 50,000, or 60,000 or is a mean of a plurality of integers havinga value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000,30,000, 40,000, 50,000, or 60,000; R⁵ is selected from the groupconsisting of H, alkyl, and R^(4b); J is selected from the groupconsisting of H, F, O-alkyl, N(R^(8a))₂, N⁺(R^(8a))₃,N(R^(8a))C(O)alkyl, CO₂H, C(═O)N(R^(8a))₂, CO₂-alkyl, P(O)(OH)₂,P(O)(O-alkyl)₂, and a substituted nitrogen-containing heterocycle;R^(8a) is absent, or selected from the group consisting of H, -(alkyl)-,-(cycloalkyl)-, C(alkyl)₂-J, —R^(4b), wherein R^(8a) can also cyclizewith the atom to which R^(8a) is bonded to form a 3, 4, 5, 6 or7-membered ring that is aromatic or non-aromatic and may contain one ormore heteroatoms, wherein the ring may be further substituted one ormore times with substitutents that are the same or different; and R⁹ isselected from the group consisting of H, alkyl and CH₂CO₂H.
 19. A methodof treating a bacterial infection comprising administering to a subjectin need thereof a pharmaceutically acceptable amount of a compound ofclaim 1, such that the bacterial infection is treated.
 20. A method oftreating an EF-Tu associated-state comprising administering to a subjectin need thereof a pharmaceutically acceptable amount of a compound ofclaim 1, such that the EF-Tu associated state is treated.
 21. A methodof treating, inhibiting or preventing the activity of EF-Tu in a subjectin need thereof, comprising administering to the subject apharmaceutically acceptable amount of a compound of claim
 1. 22. Themethod of claim 20, wherein a bacterial infection is treated in asubject in need thereof.
 23. A method of treating, inhibiting orpreventing the activity of bacteria in a subject in need thereof,comprising administering to the subject a pharmaceutically acceptableamount of a compound of claim 1, wherein the compound interacts with anytarget in the life cycle of the bacteria.
 24. The method of claim 22,wherein the target is EF-Tu.
 25. A method of treating a bacterialinfection in a subject, comprising administering to a subject in needthereof a pharmaceutically acceptable amount of a compound of claim 1,and a pharmaceutically acceptable carrier, such that the bacterialinfection is treated.
 26. A method of treating a bacterial infectioncomprising administering to a subject in need thereof a pharmaceuticallyeffective amount of a compound of claims 1, in combination with apharmaceutically effective amount of an additional therapeutic agent,such that the bacterial infection is treated.
 27. The method of claim25, wherein the compound of 1 and the other pharmaceutical agent areadministered as part of the same pharmaceutical composition.
 28. Themethod of claim 25, wherein the compound of claim 1 and the othertherapeutic agent are administered as separate pharmaceuticalcompositions, and the compound is administered prior to, at the sametime as, or following administration of the other agent.
 29. A packagedbacterial infection treatment, comprising a compound of claim 1,packaged with instructions for using an effective amount of the compoundto treat a bacterial infection.
 30. A method of treating acne in subjectin need thereof comprising administering to the subject apharmaceutically acceptable amount of a compound of claim
 1. 31. Apharmaceutical composition comprising a compound of claim 1, and atleast one pharmaceutically acceptable carrier or diluent.
 32. Thecompound of claim 1, or a salt thereof, which is selected from the groupconsisting of